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Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans
ORPHA:85165CID-10 · Q77.4CID-11 · LD24.0YOMIM 616482DOENÇA RARA

Uma síndrome caracterizada pela associação de acondroplasia grave com atraso no desenvolvimento e acantose nigricans. Ela foi descrita em quatro pessoas sem parentesco. Anomalias estruturais do sistema nervoso central, convulsões e perda auditiva também foram relatadas, juntamente com o encurvamento da clavícula, fêmur, tíbia e fíbula em alguns casos. A síndrome é causada por uma substituição Lys650Met na região quinase do receptor 3 do fator de crescimento de fibroblastos (codificado pelo gene FGFR3; 4p16.3).

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Introdução

O que você precisa saber de cara

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Uma síndrome caracterizada pela associação de acondroplasia grave com atraso no desenvolvimento e acantose nigricans. Ela foi descrita em quatro pessoas sem parentesco. Anomalias estruturais do sistema nervoso central, convulsões e perda auditiva também foram relatadas, juntamente com o encurvamento da clavícula, fêmur, tíbia e fíbula em alguns casos. A síndrome é causada por uma substituição Lys650Met na região quinase do receptor 3 do fator de crescimento de fibroblastos (codificado pelo gene FGFR3; 4p16.3).

Escala de raridade

CLASSIFICAÇÃO ORPHANET · BRASIL 2024
<1 / 1 000 000
Ultra-rara
<1/50k
Muito rara
1/20k
Rara
1/10k
Pouco freq.
1/5k
Incomum
1/2k
Prevalência
0.0
Worldwide
Casos conhecidos
5
pacientes catalogados
Início
Childhood
🏥
SUS: Cobertura mínimaScore: 35%
1 medicamentos CEAFCentros em: PA, PR, SC, RS, ES +10CID-10: Q77.4
🇧🇷Dados SUS / DATASUS
PROCEDIMENTOS SIGTAP (5)
0202010503
Cariótipo — bandas G, Q ou Rgenetic_test
0202010600
Pesquisa de microdeleções/microduplicações por FISHlab_test
0202010694
Sequenciamento completo do exoma (WES)rehabilitation
0202010260
Dosagem de alfa-fetoproteína
0301070040
Atendimento em reabilitação — doenças raras
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Entender a doença

Do básico ao detalhe, leia no seu ritmo

Preparando trilha educativa...

Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

🧠
Neurológico
14 sintomas
🦴
Ossos e articulações
6 sintomas
🫁
Pulmão
4 sintomas
😀
Face
3 sintomas
🫃
Digestivo
2 sintomas
🧬
Pele e cabelo
2 sintomas

+ 23 sintomas em outras categorias

Características mais comuns

100%prev.
HP:0003577
Frequência: 4/4
100%prev.
Hipoplasia do corpo caloso
Muito frequente (99-80%)
100%prev.
Baixa estatura grave
Frequência: 4/4
100%prev.
Deficiência intelectual
Frequência: 2/2
100%prev.
Atraso global do desenvolvimento
Frequência: 3/3
100%prev.
Apresentação pélvica
Frequência: 4/4
58sintomas
Muito frequente (12)
Frequente (18)
Ocasional (22)
Sem dados (6)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 58 características clínicas mais associadas, ordenadas por frequência.

HP:0003577
Frequência: 4/4100%
Hipoplasia do corpo calosoHypoplasia of the corpus callosum
Muito frequente (99-80%)100%
Baixa estatura graveSevere short stature
Frequência: 4/4100%
Deficiência intelectualIntellectual disability
Frequência: 2/2100%
Atraso global do desenvolvimentoGlobal developmental delay
Frequência: 3/3100%

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1desde 2026
Últimos 10 anos123publicações
Pico202014 papers
Linha do tempo
2026Hoje · 2026📈 2020Ano de pico
Publicações por ano (últimos 10 anos)

Encontrou um erro ou informação desatualizada? Sugira uma correção →

Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

1 gene identificado com associação a esta condição. Padrão de herança: Autosomal dominant, Not applicable.

FGFR3Fibroblast growth factor receptor 3Disease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferat

LOCALIZAÇÃO

Cell membraneCytoplasmic vesicleEndoplasmic reticulumSecreted

VIAS BIOLÓGICAS (2)
Signaling by FGFR3 in diseaset(4;14) translocations of FGFR3
MECANISMO DE DOENÇA

Achondroplasia

A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. ACH is an autosomal dominant disease.

EXPRESSÃO TECIDUAL(Ubíquo)
Skin Not Sun Exposed Suprapubic
364.6 TPM
Skin Sun Exposed Lower leg
356.5 TPM
Esôfago - Mucosa
199.7 TPM
Brain Caudate basal ganglia
148.4 TPM
Brain Nucleus accumbens basal ganglia
135.4 TPM
OUTRAS DOENÇAS (19)
nevus, epidermalsevere achondroplasia-developmental delay-acanthosis nigricans syndromelacrimoauriculodentodigital syndrome 2testicular germ cell tumor
HGNC:3690UniProt:P22607

Variantes genéticas (ClinVar)

416 variantes patogênicas registradas no ClinVar.

🧬 FGFR3: GRCh38/hg38 4p16.3-15.33(chr4:68454-12774004)x1 ()
🧬 FGFR3: GRCh38/hg38 4p16.3(chr4:68454-4013853)x3 ()
🧬 FGFR3: NM_000142.5(FGFR3):c.2173A>G (p.Met725Val) ()
🧬 FGFR3: NM_000142.5(FGFR3):c.380-1G>A ()
🧬 FGFR3: GRCh38/hg38 4p16.3(chr4:49556-3910769)x1 ()
Ver todas no ClinVar

Classificação de variantes (ClinVar)

Distribuição de 35 variantes classificadas pelo ClinVar.

9
21
5
Patogênica (25.7%)
VUS (60.0%)
Benigna (14.3%)
VARIANTES MAIS SIGNIFICATIVAS
FGFR3: NM_000142.5(FGFR3):c.1827C>G (p.Ala609=) [Conflicting classifications of pathogenicity]
FGFR3: NM_000142.5(FGFR3):c.2005C>G (p.Arg669Gly) [Conflicting classifications of pathogenicity]
FGFR3: NM_000142.5(FGFR3):c.200G>A (p.Gly67Asp) [Conflicting classifications of pathogenicity]
FGFR3: NM_000142.5(FGFR3):c.2153A>G (p.Asn718Ser) [Conflicting classifications of pathogenicity]
FGFR3: NM_000142.5(FGFR3):c.598C>T (p.Arg200Cys) [Conflicting classifications of pathogenicity]

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

Carregando...

Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

Carregando informações de tratamento...

Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans

Centros de Referência SUS

37 centros habilitados pelo SUS para Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans

Centros para Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans

Detalhes dos centros

Hospital Universitário Prof. Edgard Santos (HUPES)

R. Dr. Augusto Viana, s/n - Canela, Salvador - BA, 40110-060 · CNES 0003808

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Infantil Albert Sabin

R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Infantil Albert Sabin

R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)

Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)

Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da UFG

Rua 235 QD. 68 Lote Área, Nº 285, s/nº - Setor Leste Universitário, Goiânia - GO, 74605-050 · CNES 2338424

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Universitário da UFJF

R. Catulo Breviglieri, Bairro - s/n - Santa Catarina, Juiz de Fora - MG, 36036-110 · CNES 2297442

Atenção Especializada

Rota
Anomalias Congênitas

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Julio Müller (HUJM)

R. Luis Philippe Pereira Leite, s/n - Alvorada, Cuiabá - MT, 78048-902 · CNES 2726092

Atenção Especializada

Rota
Anomalias Congênitas

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Lauro Wanderley (HULW)

R. Tabeliao Estanislau Eloy, 585 - Castelo Branco, João Pessoa - PB, 58050-585 · CNES 0002470

Atenção Especializada

Rota
Anomalias Congênitas

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Pequeno Príncipe

R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Pequeno Príncipe

R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Universitário Regional de Maringá (HUM)

Av. Mandacaru, 1590 - Parque das Laranjeiras, Maringá - PR, 87083-240 · CNES 2216108

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Pedro Ernesto (HUPE-UERJ)

Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)

Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)

Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital São Lucas da PUCRS

Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital de Clínicas de Porto Alegre (HCPA)

Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Porto Alegre (HCPA)

Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário da UFSC (HU-UFSC)

R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Base de São José do Rio Preto

Av. Brg. Faria Lima, 5544 - Vila Sao Jose, São José do Rio Preto - SP, 15090-000 · CNES 2079798

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Ribeirão Preto (HCRP-USP)

R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Ribeirão Preto (HCRP-USP)

R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

UNIFESP / Hospital São Paulo

R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo
Sobre os centros SUS: Estes centros são habilitados pelo Ministério da Saúde como Serviços de Referência em Doenças Raras ou Serviços de Atenção Especializada. O atendimento é pelo SUS, com encaminhamento da rede de atenção básica.

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Publicações mais relevantes

Timeline de publicações
0 papers (10 anos)
#1

Associations Between Reproductive Disorders and Specific Physical, Mental, Personality, and Social Characteristics: A Narrative Review.

Health science reports2026 Mar

The present review aims to ascertain whether reproductive disorders are associated with specific physical, mental, personality, and social traits. This information may be used to support or reject the hypothesis on the origin of infecundity, which proposes that women/men with preferred characteristics, including high resource holding potential, genetic quality, and/or reproductive potential have advantage over women/men displaying less preferred traits in selecting partners with preferred traits. A literature search of the reported associations of endometriosis, polycystic ovary syndrome, diminished ovarian reserve in women < 35 years, and low semen quality with specific physical, mental, personality, and social characteristics was carried out using the PubMed database. Endometriosis is associated with lower body mass index and waist-to-hip ratio, greater breast-to-underbreast ratio, severe teenage acne, red hair, fair skin, nevi and freckles, light eyes, and high sensitivity to sun exposure. Polycystic ovary syndrome is linked to central adiposity, waist-to-hip ratio > 0.80, acne vulgaris, acanthosis nigricans, and hirsutism in both obese and lean women, and lower cognitive performance on memory, executive function, attention, information processing speed, and visuospatial skills. Diminished ovarian reserve in women < 35 years is associated with shorter cycle length and menstrual bleeding length, either shorter or longer than 4-6 days. Sperm quality is negatively correlated with body mass index, waist circumference, weight gain since age 17 years, extraversion, and psychoticism, but positively correlated with general intelligence. The four reproductive disorders analyzed are significantly associated with high levels of anxiety, stress, and/or depression, as well as economic burden (endometriosis) or lower socioeconomic status (polycystic ovary syndrome, diminished ovarian reserve, and low semen quality). This study discloses specific physical, mental, personality, and social traits associated with four reproductive disorders. More efforts are warranted to evaluate traits associated with reproductive disorders using a multiethnic and multicultural viewpoint.

#2

De Novo Germline L858R EGFR Variants and Generalized Acanthosis Nigricans.

JAMA dermatology2026 Mar 01

Acanthosis nigricans (AN) is commonly associated with impaired glucose tolerance, but early, severe presentation in individuals with normoglycemia may identify individuals at risk for systemic disease. While gain of function epidermal growth factor receptor (EGFR) pathogenic variants are associated with pulmonary cancers, their role in syndromic skin disease has not been clearly defined. This study identified activating EGFR variants that were associated with a syndrome characterized by generalized acquired keratoderma accentuated at flexural sites, woolly hair, palmoplantar keratoderma, and pulmonary disease with lung nodules, and the results suggest EGFR inhibitor therapeutic efficacy. To determine the genetic basis of early-onset, syndromic AN and assess response to pathogenesis-directed therapy. Patients included 2 individuals with normoglycemia with early-onset periorificial hyperpigmentation and flexural skin thickening that subsequently generalized and 1 individual with an original diagnosis of widespread epidermal nevus. Participants underwent whole-exome sequencing and studies of affected skin and keratinocytes. EGFR variant identification and assessment of pathway activation in lesional skin and keratinocytes, pulmonary function testing, lung imaging, and clinical response to EGFR inhibition. All 3 participants (aged 8, 18, and 17 years; 2 male individuals and 1 female individual) had an EGFR L858R variant, which arose as either de novo in generalized cases or a somatic variant in mosaic disease. Lesional skin and cultured keratinocytes demonstrated increased EGFR pathway activity, which was suppressed by pharmacologic inhibition in vitro. Systemic treatment with EGFR inhibitors was associated with skin disease regression, improvement in pulmonary disease, and resolution or reduction of the number of pulmonary nodules. The findings of this case series study define a syndromic disorder with increased risk of pulmonary disease and lung nodules in patients with acquired, generalized AN that is associated with activating EGFR variants. Pulmonary nodules are precursor lesions for lung cancer, and treatment with EGFR inhibitions is associated with near-complete resolution of skin and pulmonary disease. Early recognition of syndromic EGFR AN will permit identification of individuals at risk for systemic disease who are candidates for EGFR-targeted therapy.

#3

Rabson-Mendenhall syndrome caused by a novel splice-site mutation (c.1123+2 T>C) of insulin receptor: A case report and review of literature.

World journal of diabetes2026 Jan 15

Rabson-Mendenhall syndrome (RMS) is an extremely rare monogenic form of diabetes caused by mutations in the insulin receptor (INSR) gene, with only about 50 cases reported worldwide to date. Here, we report a case of RMS caused by a previously unreported c.1123+2 T>C splice mutation. The patient was diagnosed with acanthosis nigricans and hypertrichosis at birth, and the growth rate was slower than that of normal children. At age 5, the patient had severe hyperinsulinemia, congenital heart abnormalities, and pineal cysts. At age 13, he was diagnosed with diabetes and exhibited symptoms of hyperinsulinemia, low body weight, growth retardation, acanthosis nigricans, dental anomalies, an oversized penis, and a pineal cyst. Sequencing results indicated an INSR c.1123+2 T>C mutation, and bioinformatic analysis suggested that this mutation led to splicing abnormalities, thereby affecting INSR function. Both parents carried the mutated gene, whereas his brother had a normal genotype. Genetic diagnosis is vital in RMS; c.1123+2 T>C mutation of INSR causes pancreatic decline; current treatments show limited effectiveness.

#4

Insulin Resistance, Metabolic Syndrome, and Inflammatory Skin Disease.

Journal of clinical medicine2026 Jan 01

Background/Objectives: The skin is an important indicator of overall health, and its relationship with insulin resistance (IR) and metabolic syndrome (MetS) has garnered increasing attention. This review explores the connection between glucose dysregulation and various dermatological conditions, aiming to highlight integrative approaches for management. Methods: A comprehensive literature search was conducted in June and July 2024 across PubMed, Google Scholar, and Embase. Peer-reviewed studies on glucose dysregulation in dermatology were identified using terms such as "insulin," "metabolic syndrome," and "dermatological manifestations." Relevant studies were selected based on their contributions to understanding these relationships. Results: The review identified significant associations between glucose dysregulation, MetS, and conditions such as psoriasis, acne, acanthosis nigricans, seborrheic dermatitis, and hidradenitis suppurativa. Key findings indicated that elevated insulin levels and inflammatory markers correlate with the severity of these skin disorders. Notably, dietary interventions and probiotics show potential in modulating inflammation and improving metabolic health. Conclusions: There is a clear link between glucose dysregulation and several dermatological conditions, underscoring the importance of a holistic treatment approach. By addressing glucose control and incorporating lifestyle modifications, clinicians can improve patient outcomes and mitigate the complications associated with IR and MetS. Further research is essential to refine these integrative strategies and assess their effectiveness in clinical practice.

#5

A de novo INSR variant in Type A insulin resistance syndrome: familial investigation and genetic implications.

Gene2026 Feb 10

Type A insulin resistance syndrome (TAIRS) is a rare autosomal dominant disorder associated with variants in the Insulin Receptor (INSR) gene. It is characterized by insulin resistance, hyperandrogenism, and acanthosis nigricans. The severity of the condition may be influenced by homozygosity or heterozygosity, with some female patients being misdiagnosed with polycystic ovary syndrome (PCOS). A 13-year-old female proband from a family was identified with hyperinsulinemia, hyperandrogenism, acanthosis nigricans, hirsutism, acne, oligomenorrhea, and masculinization. Exome sequencing and Sanger sequencing confirmed that the proband was a carrier of the INSR (NM_000208.2): c.3734 T > A(p.V1245E) variant. This variant is not listed in the Human Gene Mutation Database (HGMD) or ClinVar. The novel variant was predicted to be deleterious by the bioinformatic tools SIFT, MutationTaster, and Condel. According to the American College of Medical Genetics and Genomics (ACMG) criteria, it was evaluated as PM6, PM2_Supporting, and PP3, and classified as uncertain significance. The variant was not detected in the proband's parents or other family members, all of whom lacked the associated clinical phenotypes. The p.V1245E variant was found to be a de novo variant. SWISS-MODEL analysis suggested that the p.V1245E variant induces structural changes in the three-dimensional configuration of the INSR protein, potentially impairing its normal function. RT-qPCR revealed a significant reduction in INSR mRNA expression in the proband. In a 293 T cell model transfected with lentivirus carrying the p.V1245E variant, both Western blotting and RT-qPCR demonstrated decreased INSR mRNA and protein expression, while immunofluorescence showed reduced INSR protein levels with altered localization. Therefore, the ACMG evaluation (PS2, PS3, PM2_Supporting, PP3) was further upgraded to pathogenic. In conclusion, this de novo variant represents the pathogenic variant responsible for TAIRS in this family, expanding the variant spectrum of the INSR gene.

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📚 EuropePMCmostrando 122

2026

Associations Between Reproductive Disorders and Specific Physical, Mental, Personality, and Social Characteristics: A Narrative Review.

Health science reports
2026

Rabson-Mendenhall syndrome caused by a novel splice-site mutation (c.1123+2 T>C) of insulin receptor: A case report and review of literature.

World journal of diabetes
2026

De Novo Germline L858R EGFR Variants and Generalized Acanthosis Nigricans.

JAMA dermatology
2026

Insulin Resistance, Metabolic Syndrome, and Inflammatory Skin Disease.

Journal of clinical medicine
2026

A de novo INSR variant in Type A insulin resistance syndrome: familial investigation and genetic implications.

Gene
2025

Coincidence of Autoimmune Diabetes Mellitus and Familial Partial Lipodystrophy.

JCEM case reports
2025

[Clinical features and variant spectrum of FGFR3-related disorders].

Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics
2025

Assessment of Clinical Profile and Biochemical Parameters in Diverse Phenotypes of Polycystic Ovarian Syndrome.

Mymensingh medical journal : MMJ
2026

Beyond PCOS: An Unusual Presentation of Type A Insulin Resistance Syndrome.

Journal of pediatric and adolescent gynecology
2025

New Perspectives on Nutraceutical Insulin Sensitizing Agents in the Treatment of Psoriasis and Other Dermatological Diseases.

International journal of molecular sciences
2025

Acquired Generalized Lipodystrophy with Extensive Autoimmune Involvement: A Case Report and Review of the Literature.

Hormone research in paediatrics
2025

Genealogical Rabson-Mendenhall syndrome caused by INSR gene mutation.

American journal of physiology. Endocrinology and metabolism
2025

A Complex Clinical Situation in Polycystic Ovary Syndrome: HAIR-AN Syndrome ''Case Report".

Case reports in medicine
2025

Rabson-Mendenhall syndrome presented as severe acanthosis nigricans in an infant harboring novel mutations in the INSR gene: a case report.

Frontiers in pediatrics
2025

Rabson-Mendenhall Syndrome Nearly Misdiagnosed as Type 1 Diabetes Mellitus: A Case Report.

Cureus
2025

Novel estrogen receptor-α gene inactivating missense variant in a woman: Therapeutic challenge and long-term follow-up data.

Bone
2025

Pre-gestational diabetes in a young woman with a pathogenic INSR missense mutation, p.(Met1180Lys).

Endocrinology, diabetes &amp; metabolism case reports
2025

Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor.

Diabetology international
2024

Mineralocorticoid Effects in Cushing's Disease: A Case Report.

Cureus
2024

Skin as a Reflection of Gut Health: An Overview of Dermatological Manifestations in Primary Neoplastic and Autoimmune Gastrointestinal Disorders.

Cureus
2024

Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients.

Journal of the Endocrine Society
2024

Hereditary Severe Insulin-resistance Syndrome and Acanthosis Nigricans Caused by Novel Mutations in the INSR Gene.

Journal of clinical research in pediatric endocrinology
2024

Primary disease of adipose tissue: When to think about and how to evaluate it in clinical practice?

Annales d'endocrinologie
2024

Review of facial acanthosis nigricans: Easy to diagnose and difficult to treat marker of hyperinsulinemia/metabolic syndrome.

Medical journal, Armed Forces India
2024

A Novel Mutation in the INSR Gene Causes Severe Insulin Resistance and Rabson-Mendenhall Syndrome in a Paraguayan Patient.

International journal of molecular sciences
2024

Type A insulin resistance syndrome due to a novel heterozygous c.3486_3503del (p.Arg1163_Ala1168del) INSR gene mutation in an adolescent girl and her mother.

Archives of endocrinology and metabolism
2024

Distinct Reproductive Phenotypes Segregate With Differences in Body Weight in Adolescent Polycystic Ovary Syndrome.

Journal of the Endocrine Society
2024

Homeopathic Medicines in Third (Omicron) Wave of COVID-19: Prognostic Factor Research.

Homeopathy : the journal of the Faculty of Homeopathy
2023

Combination of metformin with liraglutide in treating HAIR-AN syndrome in children: A case report and literature review.

Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
2023

Alström Syndrome: A Rare Cause of Severe Insulin Resistance.

JCEM case reports
2023

Resolution of Hyperandrogenism, Insulin Resistance and Acanthosis Nigricans (HAIR-AN) Syndrome After Sleeve Gastrectomy.

JCEM case reports
2023

A promising treatment for spontaneous ovarian hyperstimulation syndrome due to familial partial lipodystrophy: GnRH analogs combined with cyst aspiration.

Hormones (Athens, Greece)
2023

A Novel Leptin Receptor LEPR Variant in a Toddler With Early-Onset Fatal Obesity.

Pediatrics
2023

Unravelling the pathogenesis of foramen magnum stenosis in patients with severe achondroplasia: a CT-based comparison with age-matched controls and FGFR3 craniosynostosis syndromes.

Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
2023

Cardiometabolic risk factors among children who are affected by overweight, obesity and severe obesity.

Frontiers in public health
2023

A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation.

Endocrinology, diabetes &amp; metabolism case reports
2023

A novel nonsense mutation in the insulin receptor gene in a patient with HAIR-AN syndrome and endometrial cancer.

Molecular genetics and metabolism reports
2022

A novel missense ALMS1 variant causes aberrant splicing identified in a cohort of patients with Alström syndrome.

Frontiers in genetics
2022

INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report.

Medicine
2023

Efficacy of individualized homeopathic medicines in irritable bowel syndrome: A double-blind randomized, placebo-controlled trial.

Explore (New York, N.Y.)
2022

Acanthosis Nigricans: Pointer of Endocrine Entities.

Diagnostics (Basel, Switzerland)
2022

[The 495th case: young female-hyperandrogenemia-severe insulin resistance].

Zhonghua nei ke za zhi
2022

High Prevalence of Cardiometabolic Comorbidities Among Children and Adolescents With Severe Obesity From a Large Metropolitan Centre (Hangzhou, China).

Frontiers in endocrinology
2022

Estimation of Metabolic Syndrome in Acanthosis Nigricans - A Hospital Based Cross-Sectional Study.

Indian journal of dermatology
2022

A novel variant site of Alstrom syndrome in a Chinese child: a case report.

Translational pediatrics
2022

Clinico-investigative Study of Facial Acanthosis Nigricans.

Indian dermatology online journal
2022

FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model.

The Journal of experimental medicine
2022

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps.

European journal of endocrinology
2021

A Case of Nevoid Acanthosis Nigricans Successfully Treated with Topical Ketoconazole Plus Urea.

Acta dermatovenerologica Croatica : ADC
2023

Syndrome of Congenital Insulin Resistance Caused by a Novel INSR Gene Mutation.

Journal of clinical research in pediatric endocrinology
2021

[How to explore... hyperandrogenism associated with insulin resistance ? An example based on the HAIR-AN syndrome.].

Revue medicale de Liege
2021

Cutaneous manifestation of polycystic ovary syndrome.

Dermatology reports
2022

An African American Male Patient with Rare Type B Insulin Resistance Syndrome.

Laboratory medicine
2021

Clinical signs, interventions, and treatment course of three different treatment protocols in patients with Crouzon syndrome with acanthosis nigricans.

Journal of neurosurgery. Pediatrics
2021

Clinico-investigative attributes of 122 patients with hirsutism: A 5-year retrospective study from India.

International journal of women's dermatology
2022

Comprehensive management of Crouzon syndrome: A case report with three-year follow-up.

Journal of orthodontics
2021

Role of insulin and insulin resistance in androgen excess disorders.

World journal of diabetes
2021

Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome.

Frontiers in endocrinology
2021

Sex Hormones, Metabolic Status, and Obesity in Female Patients with Acne Vulgaris Along with Clinical Correlation: An Observational Cross-Sectional Study.

Indian journal of dermatology
2021

A New Mutation of the INSR Gene in a 13-Year-Old Girl with Severe Insulin Resistance Syndrome in China.

BioMed research international
2021

An adolescent girl with coexisting ovarian mature cystic teratoma and HAIR-AN syndrome, an extreme subtype of polycystic ovarian syndrome.

Endocrinology, diabetes &amp; metabolism case reports
2020

Successful remission of type B insulin resistance syndrome without rituximab in an elderly male.

Endocrinology, diabetes &amp; metabolism case reports
2021

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Clinical genetics
2020

A Case of Successful Treatment with Unilateral Oophorectomy in a Patient with Resistant Polycystic Ovary Syndrome.

Case reports in endocrinology
2020

Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly.

Journal of the Endocrine Society
2020

COVID-19 and diabetes mellitus: Unraveling the hypotheses that worsen the prognosis (Review).

Experimental and therapeutic medicine
2020

Acanthosis nigricans as a composite marker of cardiometabolic risk and its complex association with obesity and insulin resistance in Mexican American children.

PloS one
2020

Unusual Glycemic Presentations in a Child with a Novel Heterozygous Intragenic INSR Deletion.

Hormone research in paediatrics
2020

[Recognize rare diseases by the adipose tissue : Lipodystrophy-actually simple but nevertheless often overlooked].

Der Internist
2020

Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation.

Journal of pediatric endocrinology &amp; metabolism : JPEM
2021

Rabson-Mendenhall Syndrome in a brother-sister pair in Kuwait: Diagnosis and 5 year follow up.

Primary care diabetes
2020

Type B insulin resistance syndrome associated with connective tissue disease and psoriasis.

Endocrinology, diabetes &amp; metabolism case reports
2020

Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome.

Molecular syndromology
2020

Association Between Type B Insulin Resistance Syndrome and Mixed Connective Tissue Disease in an Arab African Man.

Oman medical journal
2020

Liraglutide administration improves hormonal/metabolic profile and reproductive features in women with HAIR-AN syndrome.

Endocrinology, diabetes &amp; metabolism case reports
2020

A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome.

Journal of pediatric endocrinology &amp; metabolism : JPEM
2020

Arg1201Gln mutation of insulin receptor impairs tyrosine kinase activity and causes insulin resistance: a case report.

Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
2019

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report.

Journal of medical case reports
2019

Postoperative expression of Cushing disease in a young male: metamorphosis of silent corticotroph adenoma?

Endocrinology, diabetes &amp; metabolism case reports
2019

Fatty Liver and Autoimmune Hepatitis: Two Forms of Liver Involvement in Lipodystrophies.

GE Portuguese journal of gastroenterology
2019

GnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation.

Journal of the Endocrine Society
2019

Majewski dwarfism type II: an atypical neuroradiological presentation with a novel variant in the PCNT gene.

BMJ case reports
2019

Effectiveness and Safety of Metformin versus Canthex™ in Patients with Acanthosis Nigricans: A Randomized, Double-blind Controlled Trial.

Indian journal of dermatology
2019

Posterior Distraction First or Fronto-Orbital Advancement First for Severe Syndromic Craniosynostosis.

The Journal of craniofacial surgery
2018

Síndrome metabólico y aterosclerosis carotídea subclínica en niños y adolescentes mexicanos con acantosis nigricans.

Gaceta medica de Mexico
2019

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene.

Journal of diabetes
2018

A new type of familial partial lipodystrophy: distinctive fat distribution and proteinuria.

Endocrine research
2019

Evaluation of nonalcoholic fatty liver disease using magnetic resonance in obese children and adolescents.

Jornal de pediatria
2018

Acanthosis nigricans and the metabolic syndrome.

Clinics in dermatology
2017

Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.

Radiographics : a review publication of the Radiological Society of North America, Inc
2018

Prevalence of dermatologic manifestations and metabolic biomarkers in women with polycystic ovary syndrome in north China.

Journal of cosmetic dermatology
2017

A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans.

Journal of clinical research in pediatric endocrinology
2017

Severe, Malignant Acanthosis Nigricans Associated with Adenocarcinoma of the Endometrium in a Young Obese Female.

Case reports in dermatology
2017

Hormonal therapies for acne.

Clinics in dermatology
2017

Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect-associated diseases.

Pediatric diabetes
2017

Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.

American journal of medical genetics. Part A
2017

Diagnostic and management challenges from childhood, puberty through to transition in severe insulin resistance due to insulin receptor mutations.

Pediatric diabetes
2017

Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports.

Journal of medical case reports
2017

Palmoplantar Keratoderma in Costello Syndrome Responsive to Acitretin.

Pediatric dermatology
2017

Achondroplasia: Development, pathogenesis, and therapy.

Developmental dynamics : an official publication of the American Association of Anatomists
2016

Skin manifestations of Cushing's syndrome.

Reviews in endocrine &amp; metabolic disorders
2016

Rabson Mendenhall Syndrome caused by a novel missense mutation.

International journal of pediatric endocrinology
2016

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions.

World journal of gastroenterology
2016

Lelis Syndrome: A Rare Cause of Acanthosis Nigricans.

Pediatric dermatology
2017

Paraneoplastic pemphigus as a presentation of acute myeloid leukemia: Early diagnosis and remission.

Hematology/oncology and stem cell therapy
2016

A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

Cells
2016

Pseudoacromegaly in congenital generalised lipodystrophy (Berardinelli-Seip syndrome).

BMJ case reports
2016

Fitting the pieces of the puzzle together: a case report of the Dunnigan-type of familial partial lipodystrophy in the adolescent girl.

BMC pediatrics
2017

[Acantosis nigricans in severe insulin resistance syndromes].

Anales de pediatria (Barcelona, Spain : 2003)
2016

First molecular diagnosis of Donohue syndrome in Africa: novel unusual insertion/deletion mutation in the INSR gene.

Molecular biology reports
2016

Cutaneous Findings and Systemic Associations in Women With Polycystic Ovary Syndrome.

JAMA dermatology
2016

A novel homozygous missense mutation in the insulin receptor gene results in an atypical presentation of Rabson-Mendenhall syndrome.

European journal of medical genetics
2016

The prevalence of obstructive sleep apnea in symptomatic patients with syndromic craniosynostosis.

International journal of oral and maxillofacial surgery
2016

Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.

Pediatric nephrology (Berlin, Germany)
2016

Successful rhIGF1 treatment for over 5 years in a patient with severe insulin resistance due to homozygous insulin receptor mutation.

Diabetic medicine : a journal of the British Diabetic Association
2015

[Detection and treatment of respiratory disorders in obese children: Obstructive sleep apnea syndrome and obesity hypoventilation syndrome].

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie
2015

Hyperandrogenism-Insulin Resistance-Acanthosis Nigricans Syndrome.

Case reports in endocrinology
2015

Identification and Functional Characterization of Two Novel Nonsense Mutations in the β-Subunit of INSR That Cause Severe Insulin Resistance Syndrome.

Hormone research in paediatrics
2015

[Familial partial lipodystrophy (Dunnigan syndrome) due to LMNA gene mutation: The first description of its clinical case in Russia].

Terapevticheskii arkhiv
2015

Costello syndrome with severe nodulocystic acne: unexpected significant improvement of acanthosis nigricans after oral isotretinoin treatment.

Case reports in pediatrics
2015

Donohue syndrome: a new case with a new complication.

Journal of pediatric endocrinology &amp; metabolism : JPEM
2015

[Familial partial lipodystrophy type 1. A rare or underdiagnosed syndrome?].

Medicina

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Referências e fontes

Bases de dados externas citadas neste artigo

Publicações científicas

Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.

  1. Associations Between Reproductive Disorders and Specific Physical, Mental, Personality, and Social Characteristics: A Narrative Review.
    Health science reports· 2026· PMID 41767346mais citado
  2. De Novo Germline L858R EGFR Variants and Generalized Acanthosis Nigricans.
    JAMA dermatology· 2026· PMID 41533385mais citado
  3. Rabson-Mendenhall syndrome caused by a novel splice-site mutation (c.1123+2 T&gt;C) of insulin receptor: A case report and review of literature.
    World journal of diabetes· 2026· PMID 41608093mais citado
  4. Insulin Resistance, Metabolic Syndrome, and Inflammatory Skin Disease.
    Journal of clinical medicine· 2026· PMID 41517578mais citado
  5. A de novo INSR variant in Type A insulin resistance syndrome: familial investigation and genetic implications.
    Gene· 2026· PMID 41360184mais citado
  6. Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome.
    Front Endocrinol (Lausanne)· 2021· PMID 33995269recente
  7. Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.
    Clin Genet· 2021· PMID 33372278recente
  8. Arg1201Gln mutation of insulin receptor impairs tyrosine kinase activity and causes insulin resistance: a case report.
    Gynecol Endocrinol· 2020· PMID 31899992recente
  9. Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report.
    J Med Case Rep· 2019· PMID 31771632recente
  10. Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene.
    J Diabetes· 2019· PMID 29877041recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:85165(Orphanet)
  2. OMIM OMIM:616482(OMIM)
  3. MONDO:0014658(MONDO)
  4. GARD:9443(GARD (NIH))
  5. Variantes catalogadas(ClinVar)
  6. Busca completa no PubMed(PubMed)
  7. Q259765(Wikidata)

Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.

Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar

Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans
Compêndio · Raras BR

Síndrome de acondroplasia grave-perturbação do desenvolvimento-acantose nigricans

ORPHA:85165 · MONDO:0014658
🇧🇷 Brasil SUS
CEAF
1AVosoritida
Geral
Prevalência
<1 / 1 000 000
Casos
5 casos conhecidos
Herança
Autosomal dominant, Not applicable
CID-10
Q77.4 · Acondroplasia
CID-11
Início
Childhood
Prevalência
0.0 (Worldwide)
MedGen
UMLS
C2674173
Wikidata
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