2q37 microdeletion syndrome (ORPHA:1001)
A rare chromosomal anomaly involving deletion of chromosome band 2q37 and characterized by a broad spectrum of clinical findings including mild-moderate developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity, hypotonia, specific facial dysmorphism, abnormal behavior, autism or autism spectrum disorder, joint hypermobility/dislocation, and scoliosis.
Epidemiology
To date, more than 150 individuals have been reported worldwide. Females are more frequently affected (60%).
Clinical description
A congenital malformation syndrome with a variable presentation. The phenotype includes mild-to-moderate developmental delay or intellectual deficit, hypotonia (50 to 65% of patients), seizures (20%-35%), brachymetaphalangism (50%), short stature (23%), characteristic facial dysmorphism (sparse scalp hair, round face, prominent forehead, upslanting palpebral fissures, sparse and arched eyebrows, deep-set eyes, midface hypoplasia, a depressed nasal bridge, deficient nasal alae and prominent columella, V-shaped appearance of the nasal tip, thin vermillion border of the lips, and a high-arched palate) and a tendency toward obesity with age. Behavioral disorders are common and may include repetitive behavior, severe communication and social interaction deficits, stereotypic movements, intermittent aggressiveness, hyperactivity, attention deficit disorder, obsessive-compulsive disorder and sleep disturbances. The following clinical features are also frequent: widely set, distally placed or supernumerary nipples, fifth finger clinodactyly, syndactyly, and small hands/feet, syndactyly of the fingers or toes, persistent fetal finger pads and a single palmar crease, and microcephaly or macrocephaly. Eczema is often present. Major malformations occur in 30% of patients with 2q37 deletions and may include congenital heart, gastrointestinal (30% of patients), genitourinary (11% of cases) and central nervous system malformations (6% of patients).
Etiology
The deletion involves the terminal region of chromosome 2 with breakpoints at or within band 2q37. A few genotype-phenotype correlations have been identified including a critical region for the Albright hereditary osteodystrophy-like phenotype. The genes in 2q37 involved in the clinical signs previously mentioned include CAPN10, PRLH, HDLBP, PER2 for the weight, GBC1, GPR35, STK25, PDCD1, GBX2, TWIST2, FARP2, PER2 for skeletal disorders, GBX2, TWIST2, FARP2, PER2, PRLH, HDLBP, TRPM8, AGAP1, KIF1A, PASK, ATG4B for behavioral disorders, and HDAC4 which is essential for the development of the brain, muscle, and bone. The deletion of Mir-562 is linked to Wilms tumor.
Diagnostic methods
Diagnosis relies on cytogenetic analysis and molecular characterization. Screening for a translocation should also be conducted as the deletion may be the result of the transmission of a derivative chromosome.
Differential diagnosis
The differential diagnosis should include other segmental aneusomy syndromes and Prader-Willi syndrome. The group of pseudohypoparathyroidism with Albright hereditary osteodystrophy should also be included in the differential diagnosis but calcium, phosphorus, and parathyroid hormone levels are in the normal range in patients with deletion 2q37.
Antenatal diagnosis
Genetic antenatal diagnosis is feasible where the deletion or associated rearrangement has previously been identified in a family member. A prenatal diagnosis might be proposed as for any de novo abnormal chromosomal rearrangement because of potential germinal mosaicism.
Genetic counseling
Most cases arise de novo; however, familial chromosomal rearrangements have been identified in a small proportion of cases. The subsequent risk to siblings of a proband depends on the specific chromosome rearrangement in the parent. Theoretically, a patient with pure 2q37 deletion will have a 50% risk to transmit the deletion.
Management and treatment
Management should be multidisciplinary and include a comprehensive evaluation of the major clinical criteria. Speech, physical and occupational therapy are required. The patients will need careful medical screening between birth and 5 years, for potential associated malformation, and follow up in referal centers for intellectual disabled patients.
Prognosis
The prognosis is very different between children some are mildly affected and other have severe intellectual disability. They have often cognitive difficulties and most of them attend special schools. At the age of 20 most of them are not autonomous and some develop psychiatric disorders.

                            Last update: 
                            June 2020


                            - Expert reviewer(s): 
                            Pr Martine DOCO-FENZY | ITHACA*


                                * European Reference Network