Short Stature, Microcephaly, And Endocrine Dysfunction

A number sign (#) is used with this entry because of evidence that short stature, microcephaly, and endocrine dysfunction (SSMED) is caused by homozygous or compound heterozygous mutation in the XRCC4 gene (194363) on chromosome 5q14.

Description

In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015).

Clinical Features

Neilan et al. (2008) reported a 14-year-old girl (patient 3) with short stature, microcephaly, and developmental delay, who at age 12 years developed motor difficulties, including gait disturbances, falls, tremors, choking and gagging on food, difficulty tying shoelaces, and problems navigating stairs. Prenatal ultrasound had shown dilated cerebral ventricles, and she required tube feedings in the first week of life. Examination revealed deep-set eyes, mild pigmentary retinopathy, beaked nose, sensorineural hearing loss, and bilateral hand weakness. Tendon stretch reflexes were increased at the patellae and absent at the ankles, with extensor plantar responses. She had fluctuating rigidity in the upper extremities, with mild coarse postural tremor bilaterally and a shuffling gait with bradykinesia, and also exhibited dysmetria and dysdiadochokinesia. Nerve conduction studies demonstrated mild sensory polyneuropathy, and neuroimaging revealed small caudate nuclei, prominent cerebral ventricles, and thin corpus callosum. Neilan et al. (2008) diagnosed the patient with Cockayne syndrome (216400). Guo et al. (2015) restudied this patient when she was 23 years of age. Her features, which included short stature, microcephaly, developmental delay, deep-set eyes, and progressive neuronal degeneration including ataxia, resembled those of patients with Cockayne syndrome; however, she had no history of photosensitivity and a relatively slow progression of symptoms. In addition, cellular tests for abnormal responses to UV light performed on a fibroblast culture from patient cells were negative. At 19 years of age, she was diagnosed with a low-grade thalamic glioma, which was not removed. Other features included hyperopia, diabetes mellitus, hypothyroidism, moderate hearing loss, and slurred speech. She had no significant infectious history, no signs of abnormal immune response, and no abnormalities in blood cell counts or immunoglobulin levels.

Shaheen et al. (2014) reported a 4-year-old Saudi Arabian girl with severe short stature and microcephaly (height, -7.1 SD; head circumference, -8.3 SD), triangular 'bird-like' face, and short philtrum, who also exhibited speech delay but had normal motor development.

From a cohort of 208 patients with a diagnosis of microcephalic primordial dwarfism, Murray et al. (2015) identified 6 patients from 5 families who had biallelic mutations in the XRCC4 gene (see MOLECULAR GENETICS). All 6 patients had significant reductions in both head and body size at birth, with median occipitofrontal head circumference (OFC) of -3.59 SD, length -4.94 SD, and weight -3.14 SD. Postnatally, patients developed extreme microcephaly (median OFC, -8.15 SD) along with significant short stature (median height, -4.6 SD). In addition, affected individuals exhibited facial similarities, including fine sparse hair, small chin, and broad nasal tip. Developmental delay was present in only some of the patients, and no recurrent developmental malformations were apparent, although 2 patients had multiple malformations, including 1 with small bilateral kidneys, ectopic kidney, and 'chronic lung disease,' and another with unilateral renal agenesis and cryptorchidism. No malignancies were reported, and there was no clinical suspicion of immunodeficiency. Detailed immunologic and hematologic investigation showed no evidence of immunodeficiency or bone marrow failure in most patients; however, 1 Saudi Arabian boy had an isolated lymphopenia involving all T-cell and B-cell subsets, although he exhibited normal responses to vaccines.

Bee et al. (2015) reported 50-year-old Italian monozygotic twin brothers, born to first-cousin parents, who had a progressive neurologic syndrome and dilated cardiomyopathy. Both brothers had short stature with short limbs, hypotelorism, cryptorchidism, and pes cavus. Gait difficulties developed in the fourth to fifth decades of life. Examination at age 50 revealed cognitive impairment in both, as well as nystagmus, slowing of eye pursuits, dysarthria, dysmetria, diffuse pyramidal signs, ataxia, and wide-based camptocormic gait with slight steppage. One brother was diagnosed with dilated cardiomyopathy at age 27 years, with hypertrophy of the interventricular septum and an ejection fraction of 25%; he received an implantable cardioverter/defibrillator at age 44. Cardiac assessment of his twin at age 50 showed a left ventricular diastolic defect with an ejection fraction of 52%. This brother also exhibited multinodular thyroid hypertrophy. Laboratory evaluation showed mildly elevated blood glucose in both brothers; in addition, both had elevated gonadotropins and low testosterone, which was attributed to hypergonadotropic hypogonadism due to bilateral cryptorchidism. Neurophysiologic studies revealed an axonal sensory neuropathy in both twins, and brain MRI showed mild atrophy of the cerebellar vermis in both. Muscle biopsy showed only type 2 fiber hypotrophy. Neuropsychologic assessment revealed severe attention deficit with constructive apraxia and deficient visuospatial memory.

De Bruin et al. (2015) studied a brother and sister from rural Chile who exhibited severe short stature, microcephaly, gonadal failure, and early-onset metabolic syndrome. Both sibs were small for gestational age and displayed progressive postnatal growth failure. The 40-year-old brother had bilateral cryptorchidism and underwent with right orchiopexy at age 7 years; his left testicle was atrophic. In addition, he underwent hemithyroidectomy for multinodular goiter at age 10; multiple thyroid nodules were also detected in his sister at age 31, but no tissue was analyzed. Both sibs failed to undergo puberty, and laboratory analysis was consistent with severe hypergonadotropic hypogonadism. At age 16, both sibs also exhibited insulin resistance despite normal oral glucose tolerance tests, and both were later diagnosed with diabetes and dyslipidemia. The brother underwent cataract surgery at age 37. Physical examination at age 40 showed severe short stature and microcephaly (height, -6.8 SD; OFC, -3.3 SD) as well as acanthosis nigricans, clinodactyly, small testes, and a high-pitched voice. Although he never showed clinical signs of immunodeficiency, he had mild lymphopenia with a decrease in natural killer and B cells, as well as CD4+ T cells. His sister had persistent anemia of unknown origin throughout childhood but no other signs of hematologic or immunologic disease. At 30 years of age, she underwent removal of a jejunal wall tumor which was determined to be a gastrointestinal stromal tumor; 1 year later, she was found to have diffuse intraabdominal metastases, which progressed despite treatment, and she died at 36 years of age.

Rosin et al. (2015) studied 3 Turkish brothers, born of first-cousin parents, who exhibited short stature, pronounced microcephaly, and mild psychomotor delay. Dysmorphic facial features included long face with sloping forehead and prominent chin, long and beaked nose, midface hypoplasia, mild hypotelorism, and synophrys. MRI in the oldest brother, aged 14 years, showed a simplified gyral pattern. The 2 older brothers had mild thrombocytopenia, but no other hematologic abnormalities. The 10.5-year-old brother also had undescended testes and the 6-month-old had inguinal hernia. Rosin et al. (2015) also studied a 14-year-old Swiss girl with short stature, microcephaly, and mild developmental delay. Dysmorphic features included long face with high forehead and prominent chin, deep-set eyes, mild strabismus, high nasal bridge, prominent and long philtrum, prominent columella, malpositioning of teeth, long neck, excessive white lines on palms, and mild truncal obesity. None of the patients had recurrent infections or other signs of immunologic problems.

Molecular Genetics

By autozygome analysis in 16 patients diagnosed with primordial dwarfism, Shaheen et al. (2014) identified a 4-year-old Saudi Arabian girl who was homozygous for a missense mutation in the XRCC4 gene (W43R; 194363.0001). XRCC4 knockdown in control fibroblasts resulted in significant impairment of DNA damage repair following ionizing radiation but not UV exposure.

Murray et al. (2015) analyzed exome sequencing data from a cohort of 208 patients diagnosed with microcephalic primordial dwarfism and identified homozygosity for the XRCC4 W43R mutation in a Saudi Arabian boy with short stature, microcephaly, and lymphopenia. Resequencing of the XRCC4 gene in that cohort identified compound heterozygosity for truncating mutations in 5 more patients from 4 families (194363.0002-194363.0006). All mutations segregated with disease in the respective families.

In 50-year-old Italian twin brothers, born of first-cousin parents, with short stature, cognitive impairment, hypergonadotropic hypogonadism, axonal sensory neuropathy, and dilated cardiomyopathy, Bee et al. (2015) excluded mutation in the TIM14 (608977) and FXN (606829) genes by direct sequencing. By whole-exome sequencing, they identified homozygosity for the previously reported R225X mutation in the XRCC4 gene (194363.0005). The brothers' unaffected father and sister were heterozygous for R225X; DNA was unavailable from their mother.

In a brother and sister from rural Chile with short stature, microcephaly, hypergonadotropic hypogonadism, and early-onset metabolic syndrome, de Bruin et al. (2015) sequenced candidate genes and excluded mutation in the IGF1 (147440) signaling pathway or in 3M syndrome (see 273750)-associated genes. Homozygosity analysis suggested that their parents were fourth-degree relatives, and exome sequencing identified a homozygous missense mutation in the XRCC4 gene (D82E; 194363.0007) that segregated with disease in the family.

In 3 Turkish brothers with short stature, microcephaly, and mild developmental delay, Rosin et al. (2015) identified homozygosity for a missense mutation in XRCC4 (R161Q; 194363.0008) that was found to cause splicing defects. In a similarly affected Swiss girl, they identified compound heterozygosity for 2 previously reported XRCC4 mutations, a 1-bp deletion (c.25delC; 194363.0002) and a nonsense mutation (R275X; 194363.0003).

In a woman with short stature, microcephaly, hypothyroidism, diabetes mellitus, and progressive ataxia, Guo et al. (2015) excluded mutation in Cockayne syndrome (see 216400)-associated genes and performed whole-exome sequencing, which revealed compound heterozygosity for the R225X mutation (194363.0005) and a 1-bp deletion (760delG; 194363.0009) in the XRCC4 gene. In contrast to individuals with LIG4 defects (see 606593), this patient had no history of chronic infections and showed a normal immune response; consistent with these clinical findings, functional analysis in patient cells demonstrated a severe defect in DSB repair but enhanced accuracy in an in vitro assay for V(D)J recombination. Guo et al. (2015) concluded that this represents a separation-of-impact phenotype, in which marked deficiency in radiation-induced DSB repair can be uncoupled from defective V(D)J recombination.