3M syndrome is a rarely inherited autosomal recessive disorder caused by mutations in cullin-7 (CUL7), obscurin-like 1 (OBSL1), and coiled-coil domain containing protein 8 (CCDC8). It is associated with multiple dysmorphic features, including characteristic facial dysmorphism (a face that is triangular, full lips, frontal bossing, a nasal tip that is fleshy, long philtrum, protruding ears and macrocephaly), severe growth retardation prenatally and postnatally and normal intelligence. Although there are multiple skeletal manifestations of the syndrome, such as joint laxity, there is no mention of developmental dysplasia of the hip (DDH) to be associated with it anywhere in the literature. Therefore, we present the first case of bilateral DDH in a patient with 3M syndrome, which was managed similarly to other DDH cases with operative reduction, pelvic osteotomies, and femoral shortening, with a satisfactory outcome after 3 years of follow-up.

3M syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the cullin 7 (CUL7), obscurin-like 1 (OBSL1), and coiled-coil domain-containing protein 8 (CCDC8) genes and is characterized by pre- and postnatal growth retardation, short stature, dysmorphic facial features, and skeletal anomalies, with normal intelligence. In this study, we report a 6-year-old female patient from China diagnosed with 3M syndrome. The patient presented with typical clinical features of growth retardation and short stature, with normal intelligence. The patient's dysmorphic facial features included relative macrocephaly, a protruding forehead, a triangular face, a pointed chin, a flat nasal bridge, full lips, a long philtrum, and a broad lower jaw. The skeletal survey was normal except for clinodactyly of the fifth fingers of both hands. Growth hormone (GH) deficiency was excluded by normal serum hormone levels and the GH stimulation test results. Whole-exome sequencing identified two heterozygous variants in CUL7, NM_014780.5: c.1639_1640del (p.Leu547Alafs*6), and NM_014780.5: c.4505T>C (p.Ile1502Thr). Parental Sanger sequencing confirmed these as compound heterozygous variants, with one variant inherited from each parent. Neither variant has been previously reported. The patient has been treated with recombinant human IGF-1 for 2 years since she was 4 years old and has achieved a growth velocity of approximately 6-7 cm per year. Herein, we describe a Chinese patient with 3M syndrome caused by novel biallelic pathogenic variants in CUL7 from a non-consanguineous family, expanding the genetic spectrum of CUL7 in the Chinese population.

A lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities. Whole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0. This article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the CUL7 gene. This is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient's clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.

3M syndrome is a rare autosomal recessive genetic disorder characterized by significant intrauterine and postnatal growth restriction. There is limited research on its genetic basis within the Chinese population. We performed trio-based whole-exome sequencing to identify the pathogenic gene in the affected child and collected and organized clinical and imaging data. Relevant information was reviewed through a literature search. In this study, we present a case involving prenatal diagnostic abnormalities and postnatal confirmation of 3M syndrome, including detailed documentation of clinical features and associated genetic variants. Notably, during prenatal ultrasound examination, the fetus exhibited increased nuchal translucency (NT) and delayed limb development. Postnatally, whole-exome sequencing revealed the compound heterozygous mutations in the CUL7 gene: c.3646-2A>G and c.3355+5G>A. The splicing mutation c.3646-2A>G is a novel pathogenic mutation, while the c.3355+5G>A mutation has been previously reported. In-silico analysis predicted strong pathogenicity for both splicing mutations. Through follow-up, we observed that the patient's height and weight are below the first percentile, with abnormal skeletal development and distinctive facial features. Based on literature review of reported cases, these mutations disrupt the normal function of CUL7-OBSL1-CCDC8 complex in the ubiquitin-proteasome pathway, leading to impaired growth regulation. This study identified a novel splicing mutation in the CUL7 gene in a patient with 3M syndrome, expanding the genetic spectrum of this disorder and contributing novel insights for clinical diagnosis and management.

3M syndrome (3MS) is a very rare autosomal recessive disorder characterized by short stature, distinctive facial features, and skeletal abnormalities. The condition is frequently underdiagnosed due to its nonspecific symptoms and normal neurocognitive development. Few reports exist on its clinical course and response to growth hormone (GH) therapy. Therefore, this study aims to describe the clinical features of Saudi patients with 3MS and to investigate the effects of growth hormone therapy on growth. We conducted a retrospective case series of 14 Saudi patients from 11 families with genetically confirmed 3MS at King Faisal Specialist Hospital and Research Centre in Riyadh. The mean age at diagnosis was 5.4 years. Consanguinity was present in 79% of cases. The most frequently affected gene was CUL7 (57% of cases), followed by OBSL1 and CCDC8. All variants were predominantly homozygous and classified as pathogenic or likely pathogenic. Clinical abnormalities included growth retardation, dental abnormalities, spinal abnormalities, and a characteristic facial appearance. GH therapy was administered to 10 children; 5 demonstrated a measurable improvement in growth velocity, while 5 did not respond or discontinued treatment. IGF-1 was within/low-normal in most tested cases, with two elevated results. Our study highlights the extensive phenotypic variability of 3MS and underscores the predominantly autosomal recessive inheritance pattern in this population. GH therapy may provide a growth benefit in select cases, although resistance and poor response remain a challenge. Genetic testing is crucial for accurate diagnosis, individualized management, and appropriate family counseling.