Chromosome 16q22 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

Description

The interstitial 16q22 deletion syndrome is a multiple congenital anomaly disorder associated with failure to thrive in infancy, poor growth, delayed psychomotor development, hypotonia, and dysmorphic features, including large anterior fontanel, high forehead, diastasis of the cranial sutures, broad nasal bridge, hypertelorism, low-set abnormal ears, and short neck. The phenotypic features and deletion sizes are variable, but deletion of 16q22 appears to be critical for manifestations of the syndrome (summary by Fujiwara et al., 1992).

Clinical Features

Fryns et al. (1977) reported an infant with an interstitial 16q21 deletion associated with craniofacial anomalies, cranial suture diastasis, and a narrow thorax who died at age 1 month of pneumonia. Postmortem examination showed intestinal malrotation and a ventricular septal defect. A review of this patient by Fujiwara et al. (1992) noted low birth weight, failure to thrive, hypotonia, and poor suck. The patient reported by Fryns et al. (1977) also had a large anterior fontanel, high forehead, prominent metopic suture, broad nasal bridge, hypertelorism, low-set abnormal ears, small upslanted palpebral fissures, micrognathia, short neck, and broad toes.

Rivera et al. (1985) reported an infant with a de novo interstitial deletion of chromosome 16q21-q23. He had very low birth weight and length, small head, joint contractures, and poor suck. Dysmorphic features included relatively large skull with brachycephaly, high forehead, prominent metopic suture, hypertelorism, small nose with flat bridge, long philtrum, thin lips, micrognathia, arched palate, low-set ears, short neck, and brachydactyly. Cardiac examination showed aortic coarctation. He died at age 6 months. Rivera et al. (1985) noted the similarities to the case reported by Fryns et al. (1977), who had a 16q21 deletion.

Naritomi et al. (1988) reported a girl with a de novo 16q13-q22 deletion. She had failure to thrive as a newborn and poor subsequent growth. She had a large anterior fontanel and widely patent cranial sutures at age 2 months. Brain CT showed mild hydrocephalus and an occipital meningoencephalocele. At age 18 months, the cranial sutures were still widely patent, and she had a high bossed forehead, epicanthal folds, hypertelorism, flat and broad nasal bridge, short nose, low-set, posteriorly rotated, deformed ears, high-arched palate, short neck, and widely spaced nipples. She was hypotonic and showed mild psychomotor retardation at age 3 years.

Fujiwara et al. (1992) reported a female infant with an interstitial deletion of chromosome 16q who had mild dysmorphic features, including prominent forehead, wide anterior fontanel, diastasis of the cranial sutures, hypertelorism, upslanting palpebral fissures, broad nasal bridge, narrow thorax, and widely spaced nipples. She had severe failure to thrive due to recurrent vomiting and watery diarrhea, developed convulsions and repeated cardiac arrest, and died on day 159 of life from repeated infections. High resolution banding showed a de novo deletion of chromosome 16q22.1-q22.3. Fujiwara et al. (1992) reviewed previous reports of 7 additional patients with different deletions of regions 16q21 to 16q24, including 1 patient with a 16q13-q22 deletion, and noted that there was a constellation of similar features. Affected individuals had low birth weight, failure to thrive, feeding disturbances, hypotonia, and delayed psychomotor development. Dysmorphic features included prominent forehead, wide anterior fontanel, diastasis of cranial sutures, blepharostenosis, hypertelorism, broad nasal bridge, low-set and deformed ears, and short neck. Less common features included narrow thorax and ectopic anus. The most common deleted region was 16q22.

Callen et al. (1993) reported the features of 4 unrelated patients with variable interstitial deletions of 16q21-q24. All the breakpoints were different. The phenotype was somewhat variable, but common features included failure to thrive, delayed psychomotor development, hypotonia, large anterior fontanel, high forehead, broad and flat nasal bridge, low-set dysmorphic ears, micrognathia, high-arched palate, flexed fingers, and broad first toe. Callen et al. (1993) also referred to a family in which 3 members had a deletion of 16q21 with a normal phenotype, suggesting that loss of 16q21 is not pathogenic.

Goto et al. (2004) reported a Japanese boy with an approximately 1.2-Mb deletion of chromosome 16q22 encompassing the CBFB gene (121360). At birth, he had low height, weight, and head circumference, but was noted to have a large and apparently bulging fontanel with delayed mineralization of the skull and no hydrocephalus. Radiographs showed open fontanel, multiple wormian bones along the sagittal suture, hypoplasia of the distal phalanges, and slightly narrow upper thorax. He later showed mild psychomotor retardation and dysmorphic features, including midface hypoplasia, upslanting palpebral fissures, epicanthal folds, prominent earlobes, broad nasal tip, and pointed chin. Goto et al. (2004) noted that the phenotype was reminiscent of cleidocranial dysplasia (119600), caused by mutation in the RUNX2 gene (600211), and that CBFB forms a heterodimer with RUNX2. The findings suggested that 1 feature of the 16q22 deletion syndrome, large fontanels, may be due to haploinsufficiency of CBFB.

Khan et al. (2006) reported a boy with a de novo 16q21-q22 deletion. He had a cleft soft palate, delayed mineralization of the parietal bones, and mild dysmorphic features including hypertelorism, upslanting palpebral fissures, midface hypoplasia, and micrognathia. He had hypoplastic distal phalanges of the hands and a ventricular septal defect that resolved by age 6 months. There was no evidence of bone marrow insufficiency. Despite a difficult period in infancy mainly due to feeding difficulties, he later showed developmental gains by age 15 months. Haploinsufficiency of the CBFB gene was detected by FISH analysis, and no mutations were found in the RUNX2 gene. Khan et al. (2006) noted the phenotypic similarities to a Cbfb-deficient mouse model (Kundu et al., 2002) and suggested that CBFB haploinsufficiency in their patient may have led to the cranial ossification defects.