Chromosome 19q13.11 Deletion Syndrome, Distal

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr19:39,803,651-40,127,916, NCBI36).

See also proximal chromosome 19q13.11 deletion syndrome (617219), which shows some phenotypic overlap.

Description

Distal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by poor overall growth, slender habitus, microcephaly, delayed development, intellectual disability with poor or absent speech, and feeding difficulties. Additional features include dysmorphic facies, signs of ectodermal dysplasia, hand and foot anomalies, and genitourinary anomalies, particularly in males (summary by Chowdhury et al., 2014).

Clinical Features

Kulharya et al. (1998) reported a 3-year-old girl with a constitutional del(19)(q12q13.1) deletion ascertained in utero after intrauterine growth retardation and decreased fetal activity. She was born at 38 weeks' gestation with single umbilical artery, hypotonia, and little subcutaneous fat. Minor facial anomalies included micrognathia, posteriorly angulated and apparently low-set ears, hypertelorism, broad nasal root, and high-arched palate. Other features included cutis aplasia of the posterior fontanel, fifth finger clinodactyly, overlapping toes, and congenital right hip dislocation. She had poor suck and feeding, requiring gastrostomy tube. There was also congenital deafness, cardiomegaly, and increased liver enzymes. At age 3 years, she could not sit on her own and had no speech development.

Using array comparative genomic hybridization (CGH), Malan et al. (2009) identified 3 unrelated patients with syndromic mental retardation associated with interstitial microdeletions involving chromosome 19q13.11. All 3 patients shared common clinical features, including pre- and postnatal growth retardation, slender habitus, severe postnatal feeding difficulties, developmental delay, poor speech development, microcephaly, and hypospadias. Each also had signs of ectodermal dysplasia, such as thin, sparse hair and eyebrows, dysplastic nails, and cutis aplasia over the posterior occiput. Facial dysmorphism included long face, high forehead, retrognathia, thin lips, V-shaped nose with hypoplastic nasal alae, and large ears. More variable features included widely-spaced nipples, long tapered fingers, single-median incisor, and single umbilical artery.

Schuurs-Hoeijmakers et al. (2009) reported another patient with a chromosome 19q13.11 deletion. The male proband was a dizygotic twin, and his twin sister was normal. At birth, the proband was noted to have cutis aplasia over the posterior occiput, hypospadias, abnormal positioning of the feet, and a third nipple on the left side of the chest, the latter of which was also present in the father. He had feeding difficulties, failure to thrive, and psychomotor delay in the first year of life. Dysmorphic features included deep-set eyes, a broad nasal tip, a broad mouth with thin lips, broad gums, irregular placed teeth, and retrognathia. Other features included long fingers with slender thumbs, dysplastic nails, a sacral dimple, and hyperlaxity of the joints. Schuurs-Hoeijmakers et al. (2009) noted the phenotypic similarities to the patients reported by Malan et al. (2009).

Adalat et al. (2010) reported a boy with chromosome 19q13.11 deletion who had growth retardation, pyloric stenosis, intestinal intussusception, and echogenic kidneys with laboratory evidence of renal dysfunction. Other features included microcephaly, poor speech, aplasia cutis, dry skin, clinodactyly, and pes cavus. Dysmorphic features included blepharophimosis, absence of eyelashes on the lower lids, narrow face, narrow nasal bridge, thin lips, short philtrum, posteriorly rotated and protruding ears, and crowded teeth.

Forzano et al. (2012) reported an Italian girl with chromosome 19q13.11 deletion syndrome. She had delayed development, growth retardation, microcephaly, slender habitus, and mild dysmorphic features, as well as thin hair, thin skin, dysplastic nails, and aplasia cutis of the scalp. Additional features included multiple pituitary hormone defects and growth hormone deficiency.

Gana et al. (2012) reported 2 unrelated patients with de novo heterozygous deletions of chromosome 19q13.11. The patients had intrauterine and postnatal growth retardation, microcephaly, and delayed development with intellectual disability and poor or absent speech. Both had dysmorphic features, but these were variable. A 14-year-old boy had narrow face, thick and medially sparse eyebrows, hypertelorism, columella below alae nasi, thin lips, retrognathia, low-set ears with large lobules, and aplasia cutis in the midline of the scalp. An 8-year-old girl had a round face with narrow and upslanting palpebral fissures, thick and medially sparse eyebrows, puffy checks, columella below alae nasi, short philtrum, and thin lips. The boy was severely disabled and wheelchair-bound with dystonic tetraplegia, contractures, and spasmodic oromandibular dystonia causing breathing difficulties. The girl had poor balance with clumsiness, dysdiadochokinesia, and mild hypotonia. Additional features included tapering fingers, fifth finger clinodactyly, hypospadias in the boy, and dental anomalies in the girl.

Chowdhury et al. (2014) reported 2 unrelated patients, a girl and a boy (patients 1 and 2), with 19q13.11 deletion syndrome. The patients had low birth weight, feeding difficulties with poor postnatal growth, and delayed development with speech delay. The boy had single umbilical artery, febrile seizures, hypospadias, cryptorchidism, inguinal hernia, atrial septal defect, and scalp aplasia cutis, without other evidence of ectodermal dysplasia. The girl had dental crowding and caries. The patients also had distal anomalies of the fingers and toes, as well as variable dysmorphic features, such as arched eyebrows, broad nasal bridge, short nose, upturned nares, poorly folded ears, short palpebral fissures, and smooth philtrum.

Venegas-Vega et al. (2014) reported a boy with this disorder. He had poor growth with feeding difficulties, microcephaly, developmental delay with poor speech, dysmorphic facial features, signs of ectodermal dysplasia, genital anomalies, including hypospadias, testicular ectopia, and bifid scrotum, and abnormalities of the fingers and toes. He also had recurrent respiratory infections, a febrile seizure, and bilateral inguinal hernias.

Meyer et al. (2017) reported 10 unrelated patients with a complex neurologic disorder associated with de novo heterozygous microdeletions of chromosome 19q13.11-q13.12. The patients presented with progressive dystonia in the first decade of life (2.5 to 7 years). Features included lower limb involvement with foot posturing, toe walking, and gait disturbance, and all but 1 child developed abnormal posturing in the upper limbs, resulting in decreased dexterity and handwriting difficulties. All but the same patient developed cervical symptoms, including torticollis and retrocollis, as well as severe cranial involvement, including facial dystonia and oromandibular dysfunction resulting in dysarthria, difficulties chewing and swallowing, and laryngeal involvement with dysphonia. Most patients developed generalized dystonia; however, none had compromise of the airways. Three patients treated with deep brain stimulation had a favorable response. Brain imaging showed abnormal signals in the globus pallidi. Six patients had an elongated face and 2 had a bulbous nasal tip; 1 patient had more severe dysmorphic features, including microcephaly, occipital cutis aplasia, low-set and posteriorly rotated ears, epicanthal folds, blepharophimosis, narrow nasal bridge, micrognathia, and dental crowding. Rare features, occurring in only 1 patient each, included retinal dystrophy, ectodermal dysplasia, absence seizures, short stature, absent testis, and small echogenic kidneys. Eight patients had some degree of intellectual disability. The deletions in the patients varied in size, involving 14 to over 100 genes, but the smallest region of overlap among these patients included the KMT2B (606834) and ZBTB32 (605859) genes. The deletion occurred de novo in all cases with parental testing. Meyer et al. (2017) concluded that haploinsufficiency for KMT2B was responsible for the phenotype (see 617284).

Cytogenetics

In a child with syndromic mental retardation and poor growth, Kulharya et al. (1998) identified a 15-cM deletion of 19q12-q13.1 on the paternal chromosome.

By array CGH analysis of 3 unrelated individuals with syndromic mental retardation, Malan et al. (2009) identified interstitial overlapping deletions of chromosome 19q12-q13.12, 19q13.11-q13.12, and 19q12-q13.11, respectively. The minimal critical region corresponded to 2.87 Mb on chromosome 19q13.11. The authors postulated that the phenotype results from haploinsufficiency of dosage-sensitive genes within this region.

In a patient with syndromic mental retardation, Schuurs-Hoeijmakers et al. (2009) identified a de novo 2.4-Mb deletion on chromosome 19q13.11-q13.12. The maternal allele was deleted in the proband; however, the mother carried a chromosome 19 submicroscopic insertion ins(19)(q13.3q13.11q13.12)(q13.11), indicating that recombination during meiosis may have occurred in her son. The smallest region of overlap between this patient and the patients reported by Malan et al. (2009) was 750 kb. Schuurs-Hoeijmakers et al. (2009) hypothesized that the LSM14A (610677) and UBA2 gene may be involved.

The chromosome 19 deletion in the patient reported by Forzano et al. (2012) spanned 1.37 Mb and included 49 genes. It partially overlapped previously reported deletions with the smallest region of overlap (SRO) being 460 kb. The UBA2 gene (613295) was not deleted in this patient.

The chromosome 19 deletions identified in the 2 patients reported by Gana et al. (2012) were 1.7 Mb and 2.63 Mb; the SRO was 324 kb and encompassed several genes, including ZNF302, ZNF181 (606741), ZNF599, and ZNF30. One of the patients with hypospadias had deletion of the WTIP gene (614790).

The de novo chromosome 19 deletions in the 2 patients reported by Chowdhury et al. (2014) were 8.16 Mb and 2.30 Mb and overlapped the 324-kb SRO identified by Gana et al. (2012).

The patient reported by Venegas-Vega et al. (2014) had a de novo chromosomal rearrangement with a 2.49-Mb deletion of 19q13.1 that included 49 genes, including UBA2, which the authors suggested may contribute to the urogenital anomalies as well as to the intellectual disability observed in this disorder.