Typical Face, Developmental Delay, and Hearing Loss in a Patient with 3M Syndrome: The Co-Occurrence of Two Rare Conditions

Abstract

<b><i>Introduction:</i></b> 3M syndrome is an autosomal recessive disorder characterized by characteristic facial features, severe pre- and postnatal growth restriction (<–4 SDS), and normal mental development. 3M syndrome is genetically heterogeneous. Up to date, causative mutations have been demonstrated in 3 genes, cullin-7 (<i>CUL7</i>), obscurin-like 1 (<i>OBSL1</i>), and coiled coil domain containing protein 8 (<i>CCDC8</i>). <b><i>Case presentation:</i></b> Here, we report a patient who was referred to our clinic due to short stature and developmental delay. Physical examination revealed prenatal onset short stature, low birth weight, and normal head circumference. She displayed several dysmorphic facial features in addition to developmental delay and bilateral sensorineural hearing loss. The physical findings were suggestive of 3M syndrome. Genetic assessment revealed a novel homozygous frameshift c.418_419delAC (p.Thr140Cysfs*11) variant in the <i>CUL7</i> gene and a previously reported pathogenic nonsense homozygous c.942C>A (p.Cys314Ter) variant in the <i>ILDR1</i> gene. The parents were heterozygous for the same variant. <b><i>Discussion:</i></b> 3M syndrome should be considered in the differential diagnosis of patients with short stature and typical facial features even if in the presence of other inconsistent features such as developmental delay. In addition, it is important to take into account the co-occurrence of rare autosomal recessive genetic disorders especially in countries with a high consanguineous marriage rate.

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review

“…Among these cases, 84 presented dual recessive diagnoses (AR + AR) and 22 presented multiple molecular diagnoses, with at least two recessive diagnoses (AR + AR + _). Furthermore, 72.64% (77 of 106) of these patients were known to be children of consanguineous parents [ 1 , 2 , 3 , 4 , 11 , 12 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. None of the reported cases carried recessive pathogenic variants simultaneously in the ASPM and CTNS genes, as the patient herein described.…”

Case report: Artemis deficiency and 3M syndrome—coexistence of two distinct genetic disorders

“…Chinn et al reported an adult case with biallelic variations in ZAP70 and RNF168 having had a pediatric presentation ( 15 ). Another case report described developmental delay, and hearing loss in a patient with 3M syndrome due to co-existence variants in CUL7 and ILDR1 gene ( 16 ). Also, Amato et al reported a case of Angelman syndrome (5,5 Mb deletion of 15q11.2–q13.1) with a coexisting intermediate junctional epidermolysis bullosa (COL17A1, c.3766 + 1G > A, homozygous) and autosomal recessive deafness type 57 (PDZD7, c.883C > T, homozygous) ( 17 ).…”

“…Chinn et al reported an adult case with biallelic variations in ZAP70 and RNF168 having had a pediatric presentation (15). Another case report described developmental delay, and hearing loss in a patient with 3M syndrome due to co-existence variants in CUL7 and ILDR1 gene (16). Also, Amato et al reported a case of Angelman syndrome (5,5 affiliated organizations, or those of the publisher, the editors and the reviewers.…”