This study aims to expand the spectrum of Coffin-Siris syndrome (CSS), a rare and heterogeneous disorder, by thoroughly discussing its genetic, dysmorphic, and endocrine features through new cases and contributing to the literature. Eight patients who were referred to the genetics clinic with various complaints and subsequently diagnosed with CSS through microarray or clinical exome sequencing analyses were included in the study. The dysmorphic, genetic, and endocrine characteristics of eight genetically confirmed patients were evaluated. The patients, aged between 5 months and 6 years at the time of referral, comprised four females and four males. The most common reasons for referral were developmental delay and dysmorphic features. All patients exhibited varying degrees of dysmorphic facial features. Hypertrichosis, a typical feature of the syndrome, was present in five patients. Another characteristic finding was mild hypoplasia of the terminal fifth phalanges, observed in patients 1, 2, and 6. Consistent with this, mild/subtle hypoplasia and/or slight positional changes of the fifth fingernails were noted in these patients, rather than overt nail anomalies. In our study, eight variants were identified, two of which were novel. In our cohort, pathological short stature was observed in three patients, while hypothyroidism, transient hypercalcemia, cryptorchidism, and recurrent fractures were each identified in one patient. All three patients with short stature had delayed bone age with head circumference and BMI <  - 2 SDS. Seven patients were diagnosed with ARID1B-related CSS type 1, while one patient was diagnosed with SMARCA4-related CSS type 4. Among the eight findings across patients, two were deletion-type copy-number variations (CNVs) identified by microarray analysis, and six were sequence variants: two frameshift, two splice-site, one nonsense, and one synonymous. Seven variants were classified as pathogenic and one as likely pathogenic. Family studies confirmed that the variants were de novo and validated their clinical relevance.  CSS is a clinically and genetically heterogeneous syndrome. Patients may present with highly variable features, and typical signs of the syndrome may not be observed in all cases. This study expands the clinical spectrum of this rare syndrome and contributes to its genetic spectrum with the identification of new variants. • Coffin-Siris syndrome (CSS) is a clinically and genetically heterogeneous neurodevelopmental disorder most commonly caused by variants in SWI/SNF (BAF) complex genes (e.g., ARID1B, SMARCA4) and characterized by dysmorphic features, developmental delay, hypertrichosis, and fifth-digit/nail anomalies. • Endocrine and growth-related manifestations can occur in CSS, but their frequency and phenotypic range vary across cohorts and require individualized clinical follow-up. • This case series of eight genetically confirmed CSS patients (7 ARID1B, 1 SMARCA4) expands the phenotypic spectrum by detailing dysmorphic findings together with endocrine features including pathological short stature with delayed bone age, hypothyroidism, transient hypercalcemia, cryptorchidism, and recurrent fractures. • We identified eight pathogenic/likely pathogenic variants, including two novel variants, and highlight that fifth digit/nail involvement may be subtle (mild terminal fifth phalanx hypoplasia and minor fifth nail changes) rather than overt.

Iodine plays a critical role in producing thyroid hormones essential for brain development. An imbalance of iodine, whether deficiency or excess, can disrupt thyroid function. Iodine-induced hypothyroidism is rare but has been reported, particularly in premature infants exposed to excess iodine. Currently, iohexol, a nonionic radiocontrast agent, has limited data but is considered compatible with breastfeeding. A small for gestation African American male neonate was born at 36 weeks and 3 days of gestation and admitted to the neonatal intensive care unit for respiratory distress and prematurity in the United States. Samples for Illinois newborn screens done at admission and repeated after 48 h of life were negative for thyroid abnormalities. On the infant's fifth day of life, the mother underwent a contrast-enhanced imaging study using iohexol, after which the infant received breast milk from days 5-11. On day 11, the neonate had an elevated thyroid-stimulating hormone (TSH) and low free thyroxine (T4) levels, consistent with hypothyroidism. Urine iodine level in the infant was checked and found to be elevated, prompting concern for the exposure to iodine in breastmilk. However, the need to increase the levothyroxine dose to achieve normal thyroid levels was not consistent with a transient effect such as iodine exposure. Genetic testing revealed a likely pathogenic intragenic deletion in the gene RPS6KA3, consistent with Coffin-Lowry syndrome, as well as two variants of unknown significance (VUS) in IYD. This case highlights the complex interplay between genetic factors and environmental influences in the development of neonatal hypothyroidism. While iodine contrast exposure through breast milk is generally considered safe, this case underscores the potential risks in preterm infants. Initially, iodine exposure through breastmilk was considered a likely contributor to thyroid dysfunction, but with further time and evaluation, congenital thyroid dysgenesis with underlying genetic findings complicated the diagnosis. This case demonstrates the importance of a comprehensive evaluation when working up thyroid dysfunction to exclude other potential etiologies before interrupting breastfeeding.

A certain population of patients exhibits discordant thyroid function tests (TFT) consistently along with unclear symptoms may lead to equivocal diagnosis and treatment. Concomitant elevation in TSH and T4 is one of the patterns of discordant TFT which can be associated with different thyroid-related conditions and, hence, warrants differential diagnosis. A case of congenital hypothyroidism was investigated to determine the etiology of the consistent co-elevation in TSH and T4 despite thyroxine supplementation since birth. T4 dose was changed multiple times which caused abrupt fluctuations in TSH and T4 levels in the previous treatment. The index patient, II-1 did not have pituitary or liver abnormality or any transient factors that would elevate thyroid hormone-binding proteins. The results revealed that II-1 had TBG-excess. However, no mutation or copy number variation in the SERPINA7 gene which codes for TBG was detected. Further, II-1 was detected with a homozygous mutation, c.955G > A in the exon 8 of the TPO gene associated with CH. His mother and siblings were heterozygous for the TPO mutation, however, they had normal TBG and TFT. The present study is the first report of the rare combination of endocrine disorders i.e., TBG-excess and CH, and is also the first report of the TPO mutation c.955G > A from Indian ethnic origin. The co-occurrence of two endocrine abnormalities caused TFT discordance and confusion. This study highlights the importance of detailed biochemical and genetic testing for the differential diagnosis of thyroid disorders in patients exhibiting discrepant TFT results which would avoid misdiagnosis and inappropriate treatment. Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Characteristic physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: growth deficiency, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, genitourinary tract anomalies, and ocular manifestations. Endocrine disorders (hypothyroidism, diabetes / impaired glucose tolerance), hearing loss, developmental delay, congenital heart defects, and gastrointestinal malformations are also more common in those with FA. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is 35% by age 40 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) and/or one of the following identified on molecular genetic testing: biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA; a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA; or a hemizygous pathogenic variant in FANCB known to cause X-linked FA. Targeted therapies: Oral androgens (e.g., oxymetholone, danazol) may transiently improve red blood cell and platelet counts in approximately 50% of individuals with FA. Granulocyte colony-stimulating factor improves the neutrophil count in some individuals. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, but the non-hematologic manifestations remain, including a high risk for solid tumors, which may be increased following HSCT. All these therapies have potential significant toxicity. Treatment of manifestations: Treatment of growth deficiency, limb anomalies, other orthopedic manifestations, kidney malformations, genital anomalies, hypothyroidism, diabetes, ocular anomalies, hearing loss, and cardiac anomalies as recommended by the subspecialty care provider. Early intervention for developmental delays; individualized education plan for school-age children; speech, occupational, and physical therapy as needed. Supplemental feeding as needed by nasogastric tube or gastrostomy tube. Treatment of bone marrow failure / MDS / AML through a center with experience in FA; early detection and surgical removal for solid tumors; human papilloma virus vaccination to reduce the risk for gynecologic cancer in females and reduce the risk of oral cancer in all individuals; liberal use of sunscreen and rash guards; treatment of skin cancer per dermatologist in coordination with multidisciplinary experts in FA; social work and care coordination as needed. Surveillance: Clinical assessment of growth, feeding, nutrition, spine, and ocular issues at each visit throughout childhood. Annual ophthalmology examination; assessment of pubertal stage and hormone levels at puberty and every two years until puberty is complete; annual evaluation with endocrinologist including TSH, free T4, 25-hydroxyvitamin D, two-hour glucose tolerance testing, and measurement of insulin concentration; follow-up hearing evaluation if exposed to ototoxic drugs; annual developmental assessment throughout childhood; blood counts every three to four months or as needed; bone marrow aspirate and biopsy to evaluate morphology and cellularity; FISH and cytogenetics to evaluate for emergence of a malignant clone at least annually after age two years; liver function tests every three to six months and liver ultrasound every six to twelve months in those receiving androgen therapy; gynecologic assessment for genital lesions annually beginning at age 13 years; vulvo-vaginal examinations and Pap smear annually beginning at age 18 years or with onset of sexual activity; oral examinations for tumors every six months beginning at age nine to ten years; annual nasolaryngoscopy beginning at age ten years; dermatology evaluation every six to 12 months; annual abdominal ultrasound and brain MRI in those with BRCA2-related FA. Additional cancer surveillance for individuals with BRCA1-, BRCA2-, BRIP1-, PALB2-, and RAD51C-related FA per National Comprehensive Cancer Network (NCCN) screening guidelines. Agents/circumstances to avoid: Transfusions of red blood cells or platelets for persons who are candidates for HSCT; family members as blood donors if HSCT is being considered; blood products that are not filtered (leuko-depleted) or irradiated; toxic agents that have been implicated in tumorigenesis; excessive sun exposure; unsafe sex practices, which increase the risk of HPV-associated malignancy. Radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications) should be minimized. Evaluation of relatives at risk: Molecular genetic testing (if the family-specific pathogenic variant[s] are known) or DEB/MMC cytogenetic testing of all sibs of a proband (and all at-risk family members of an individual with autosomal dominant [RAD51-related] or X-linked [FANCB-related] FA) for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers. FA is inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA). Autosomal recessive FA: If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants. Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous pathogenic variants in a subset of FA-related genes (e.g., BRCA1, BRCA2, PALB2, BRIP1, and RAD51C) are associated with an increased risk for breast and other cancers. Heterozygote testing for at-risk relatives requires prior identification of the FA-related pathogenic variants in the family. Autosomal dominant FA: Given that all probands with RAD51-related FA reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low. X-linked FA: The risk to sibs of a male proband depends on the genetic status of the mother. If the mother of the proband has a FANCB pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected. Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected. Heterozygote testing for at-risk female relatives requires prior identification of the FANCB pathogenic variant in the family. Molecular genetic prenatal testing and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.

Congenital hypothyroidism (CH) is one of the most common inherited metabolic disorders in children, and delayed diagnosis and treatment can adversely affect intellectual development and growth. In April 2025, the Chinese Society of Endocrinology and the Chinese Society of Pediatrics jointly released the "Guidelines for the diagnosis and treatment of congenital hypothyroidism". Based on the latest evidence-based medical data and clinical experience, these guidelines systematically established a comprehensive management framework covering screening, diagnosis, treatment, and follow-up, aiming to standardize CH screening, diagnosis, treatment, and long-term management. This article provides an interpretation of the main content of the guidelines. The guidelines emphasize that early diagnosis and treatment can improve the prognosis of CH and set a newborn screening cut-off value of≥8-10 mU/L as the standard for recall and examination. In terms of treatment, the guidelines stress the principle of "early and adequate" intervention, recommending levothyroxine (LT4) as the first-line treatment with a starting dose of at least 10 μg/kg. Timely follow-up and avoidance of overtreatment are also highlighted. For transient CH, it is recommended to discontinue LT4 treatment after the age of 3 and conduct further evaluations of thyroid function and imaging examinations. The guidelines also note that genetic testing to identify the molecular etiology of CH has significant guiding value for the treatment of specific types of CH. The guidelines achieve standardization of the diagnostic and therapeutic process, address the gap in lifelong management of CH in China from the neonatal period to adulthood, and provide healthcare professionals with an accurate, effective, and comprehensive normative document. 先天性甲状腺功能减退症（CH）是最常见的儿童遗传代谢性疾病之一，未及时诊治会影响儿童智力和生长发育。2025年4月中华医学会内分泌学分会与儿科学分会联合发布了《先天性甲状腺功能减退症诊治指南》，基于最新循证医学证据与临床实践经验，系统构建了从筛查、诊断、治疗到随访的全周期管理方案，旨在规范CH的筛查、诊断、治疗及长期管理。本文对指南的主要内容进行了解读。指南提出早诊断、早治疗可以改善CH的预后，并且将新生儿筛查的切点值≥8~10 mU/L作为召回复诊的标准。治疗上强调“早期、足量”原则，首选左甲状腺素（LT4），起始剂量至少要从10 μg/kg开始，注意及时随访，避免过度治疗。对于暂时性CH，建议3岁后停用LT4治疗并进一步评估甲状腺功能和影像学检查。指南同时指出基因检测明确CH患者的分子病因对于特殊类型的CH治疗具有重要的指导价值。该指南实现了诊疗流程的标准化，填补了我国CH从新生儿筛查到成年期的全生命周期管理的空白，为广大相关医务人员提供了精确、有效、全面的规范性文件。.

Transient congenital hypothyroidism (TCH) refers to temporary deficiency of thyroid hormone identified after birth which later recovers to improved thyroxine production. Its prevalence in the Philippines has not been reported in a large-scale study. Its diagnosis remains difficult due to its numerous possible etiologies. Identifying the predictive factors of TCH may aid in earlier diagnosis and decreased risk of overtreatment. This study aimed to determine the predictive factors for TCH in children with congenital hypothyroidism (CH) detected by newborn screening (NBS) in the Philippines from January 2010 to December 2017. In this multicenter retrospective cohort study involving 15 NBS continuity clinics in the Philippines, medical records were reviewed, and clinical and laboratory factors were compared between children with TCH and those with permanent congenital hypothyroidism (PCH). Of the 2,913 children diagnosed with CH in the Philippines from 2010 to 2017, 1,163 (39.92%) were excluded from the study due to an unrecalled or lost to follow-up status, or a concomitant diagnosis of Down Syndrome. Among the 1,750 patients included in analysis, 6.97% were diagnosed with TCH, 60.80% were female, mean gestational age at birth was 38 weeks, and mean birth weight was 2,841 grams. Confirmatory thyrotropin (TSH) was lower and confirmatory free thyroxine (FT4) was higher in the TCH group compared to those with PCH (TSH 32.80 vs 86.65 µIU/mL [p <0.0001]; FT4 9.90 vs 7.37 pmol/L [p 0.001]). The TCH group required lower L-thyroxine doses compared to the PCH group at treatment initiation and at 1, 2, and 3 years of age (initial 6.98 vs 12.08 µg/ kg/day [p <0.0001]; at 1 year 1.89 vs 4.11 µg/kg/day [p <0.0001]; at 2 years 1.21 vs 3.72 µg/kg/day [p <0.0001]; at 3 years 0.83 vs 3.45 µg/kg/day [p <0.0001]). Among those with TCH, mean serum TSH decreased significantly after treatment with L-thyroxine (32.80 vs. 6.55 µIU/ mL, p 0.0001). Other factors associated with TCH were results of thyroid ultrasonography (p 0.007), gestational age at birth (p 0.02), and maternal history of thyroid illness (p <0.0001). Of all the patients with confirmed congenital hypothyroidism via the newborn screening, 6.97% were diagnosed with transient CH. Factors associated with TCH are confirmatory TSH and FT4, L-thyroxine dose requirements, thyroid ultrasound findings, gestational age at birth, and a maternal history of thyroid illness.