Frank-Ter Haar Syndrome

A number sign (#) is used with this entry because Frank-ter Haar syndrome (FTHS) is caused by homozygous mutation in the TKS4 gene (SH3PXD2B; 613293) on chromosome 5q35.

Description

The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004).

Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).

Clinical Features

Frank et al. (1973) described an 18-month-old Bedouin girl, born to consanguineous parents, with megalocornea, multiple skeletal anomalies, and developmental delay, and suggested that this combination of anomalies was a hitherto unreported entity. Ter Haar et al. (1982) described 3 cases in which the bone changes and facial features (big eyes, micrognathia) were thought to be consistent with the diagnosis of Melnick-Needles syndrome; see 309350. Associated anomalies (bilateral glaucoma in 1 and congenital heart defect in 2) brought them to medical attention. Delay in closure of the anterior fontanel and sclerosis of the base of the skull and mastoids were described. The 'precocious osteodysplasia' of Danks, Mayne, and Kozlowski (see 259270) is an autosomal recessive disorder that bears some similarities. See also entries for serpentine fibula-polycystic kidney syndrome (102500) and megalocornea-mental retardation syndrome (249310) for descriptions of similar entities.

Billette de Villemeur et al. (1992) reported a girl, the child of consanguineous parents, with congenital glaucoma, hypertelorism, short saddle nose, micrognathia, flexion deformity of fingers, unilateral clubfoot, widely open fontanels, ventricular septal defect, and motor retardation. She died at 21 months. A brother, who died at 1 year, had the same condition.

Borrone et al. (1993) reported the cases of 2 brothers with a severe progressive disorder characterized by thick skin, acne conglobata, 'coarse' face, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. The younger brother died at age 24 years from heart failure. Autopsy was not performed. In the older brother, thoracolumbar gibbus was noted at 8 months of age. Eruption of teeth did not occur until age 2. Gingival hypertrophy and brachydactyly were noted in the first year. Psychomotor development was normal. At the age of 11 he showed bilateral inguinal hernias along with the other features. The vertebrae at age 11 showed reduced sagittal diameter and anterior beaking. At age 36 he showed severe disfiguring acne conglobata, particularly on the back and face, flexion contractures of large joints, marked gingival hypertrophy with loss of all teeth, kyphoscoliosis, and height of 164 cm. Biochemical and pathologic studies excluded known metabolic diseases. Both parents came from a very small Ligurian village but denied consanguinity.

Hamel et al. (1995) reported a patient with congenital glaucoma, brachycephaly with flat occiput, large anterior fontanel, hypertelorism, anteverted nostrils, thoracolumbar kyphosis, prominent coccyx with skin fold, short hands and feet, flexion deformity of fingers, and clubfeet. He had a double-outlet right ventricle with ventricular septal defect, and severe tricuspid insufficiency. Mild skeletal changes included short tubular bones, absence of distal phalanges of toes, caliber variation of ribs, and scalloping of the anterior surface of the vertebrae. The patient died at 21 months. He belonged to the same extended family as 3 similarly affected patients described by ter Haar et al. (1982) as representing an autosomal recessive form of Melnick-Needles syndrome. Hamel et al. (1995) believed this diagnosis was no longer tenable. They stated that although the craniofacial and radiologic resemblance of their patient and the 3 of ter Haar et al. (1982) to the Melnick-Needles syndrome was striking, the presence of congenital glaucoma, prominent coccyx with skin fold, and early death due to severe cardiovascular anomalies justified the conclusion that these 4 patients do not have a form of Melnick-Needles syndrome. Hamel et al. (1995) stated that their cases, the 3 reported by ter Haar et al. (1982), and the patient described by Billette de Villemeur et al. (1992) all had the same syndrome, an autosomal recessive syndrome for which they proposed the name ter Haar syndrome.

Wallerstein et al. (1997) described a boy with ter Haar syndrome, the offspring of Puerto Rican parents who were first cousins once removed. He was followed through the age of 13 years and at that time was reported to be the oldest patient with the disorder. Among the patients reported by ter Haar et al. (1982), Hamel et al. (1995), and Wallerstein et al. (1997), only the patient of Wallerstein et al. (1997) was reported to have developmental delay.

Megarbane et al. (1997) reported a family with first-cousin Syrian parents in which 2 children presented with congenital glaucoma, large anterior fontanel, prominent forehead, hypertelorism, downslanting palpebral fissures, broad and flat nasal bridge, broad nasal tip, anteverted nostrils, high-arched palate, gingival hypertrophy, pectus excavatum, prominent coccyx with skin fold, short fingers and toes, single palmar creases, flexion deformities of fingers, clubfeet, and osseous malformations. The eyes showed bilateral severe buphthalmos. Megarbane et al. (1997) concluded that their 2 patients and the patients described by ter Haar et al. (1982), Billette de Villemeur et al. (1992), and Hamel et al. (1995) all had ter Haar syndrome.

Rosser et al. (1996) described 3 patients with features common to serpentine fibula syndrome (SFS; 249420) and Frank-ter Haar syndrome. Maas et al. (2004) suggested that the patients of Rosser et al. (1996) probably had Frank-ter Haar syndrome.

AlKaissi et al. (2003) reported brother and sister, whose parents were distantly related, with congenital glaucoma, short stature, and mental retardation. Similarities were noted with ter Haar syndrome, but severe mental retardation was an additional feature.

Maas et al. (2004) delineated the entity they referred to as Frank-ter Haar syndrome in a report on 4 additional patients, including 3 sibs of Turkish descent. The authors noted that some manifestations such as progressive 'coarsening' of the face, hirsutism, gallstones, lingual papillomatosis, and cardiac valve abnormalities pointed to a possible metabolic basis for the disorder.

Van Steensel et al. (2007) reported 2 Dutch brothers, born of consanguineous parents, who had a constellation of symptoms similar to that described by Borrone et al. (1993). Both brothers had severe acne and underwent valvuloplasty for mitral valve prolapse with left ventricular dilation. The authors stated that the brothers' facial phenotype was 'identical' to that illustrated in the report of Borrone et al. (1993): coarse and prognathic, with a high, broad forehead, deep-set eyes with downward-slanting palpebral fissures and thickened lower eyelid folds, wide mouth, thick lips, and short philtrum. Their fingers were shortened and broad with slightly flat and broad nails, particularly the thumbs. The older brother had vertebral column abnormalities that were initially diagnosed as 'Scheuermann-like,' and also underwent mastectomy due to gynecomastia. Growth hormone, oligosaccharide, and amino acid levels were normal, and there were no vacuolated lymphocytes. Previously reported features not present in the Dutch brothers included gum hypertrophy, microscopic skin changes, and osteolysis, but van Steensel et al. (2007) noted that their patients were much younger at initial presentation (ages 17 and 19 years, respectively) than those described by Borrone et al. (1993) and that given the apparently progressive nature of the disease, they might yet develop those symptoms.

Wilson et al. (2014) reported an 8-year-old Australian boy, born of second-cousin parents, diagnosed with Borrone dermatocardioskeletal syndrome. The boy had coarse facies, broad forehead, broad nasal bridge, hypertelorism with prominent subocular folds, flat supraorbital ridges, and a long double-row of eyelashes. He also had prominent maxilla, broad mouth, long flat philtrum, thin lips, and broad alveolar ridges. Tooth eruption required surgical intervention due to gingival hyperplasia; histologic analysis of gingival tissue revealed fibroblasts with cytoplasmic accumulations of membrane-bound structures containing collagen fibers. Skeletal dysplasia was more severe than that in previously reported patients, with brachydactyly and ulnar deviation of digits, thickened interphalangeal joints, flexion deformity of metacarpal joints, bilateral dislocation of radial heads, genu valgum, and clubfoot. Premature fusion of sagittal and lambdoid sutures resulted in abnormal cranial morphology. Progressive severity of multiple fixed contractures of large and small joints resulted in confinement to a wheelchair at age 5 years. X-rays at age 7 years showed generalized osteopenia of the radius and ulna, with marked widening of the medullary cavity of bones and thinning of overlaying cortex. Multiple anomalies were evident in the vertebral column, including kyphoscoliosis, gibbus deformity, anterior beaking of L2 vertebra, and scalloping of lower thoracic and upper lumbar vertebrae. The boy died at 8 years of age from acute congestive heart failure due to mitral valve prolapse, as well as from respiratory failure associated with the restrictive lung deficit caused by his thoracic wall deformity.

Inheritance

Borrone et al. (1993) suggested that the multisystem disorder they described was inherited in an autosomal recessive or X-linked manner.

Autosomal recessive inheritance of Frank-ter Haar syndrome was confirmed by Iqbal et al. (2010).

Mapping

Iqbal et al. (2010) performed homozygosity mapping in 16 patients from 12 apparently unrelated families with Frank-ter Haar syndrome, including the Dutch family originally described by ter Haar et al. (1982), and identified a 0.27-Mb region of shared homozygosity on chromosome 5q35.1.

In an 8-year-old Australian boy diagnosed with Borrone dermatocardioskeletal syndrome, Wilson et al. (2014) performed linkage analysis and identified 6 linkage regions that attained the maximum possible adjusted lod score of 1.75, including 1 on chromosome 5. In the family originally described by Borrone et al. (1993), Wilson et al. (2014) identified a single homozygous peak at chr5:169,352,662-172,043,315 (GRCh37) with a maximum adjusted lod score of 4.1, located entirely within the chromosome 5 peak observed in the Australian patient. In addition, Wilson et al. (2014) studied the Dutch brothers with Borrone syndrome who were previously reported by van Steensel et al. (2007) and identified 5 linkage peaks, none of which corresponded with the peaks seen in the Australian patient, suggesting locus heterogeneity.

Molecular Genetics

In the Lebanese family of Syrian origin with Frank-ter Haar syndrome originally reported by Megarbane et al. (1997), Iqbal et al. (2010) analyzed SNP array data for copy number variation and identified a homozygous deletion on chromosome 5q in affected individuals. The smallest interval overlapping a region of shared homozygosity identified in other FTHS families contained only 1 gene, SH3PXD2B (613293). Iqbal et al. (2010) screened the SH3PXD2B gene in probands from 12 FTHS families and identified 4 homozygous mutations in 6 families (613293.0001-613293.0004), including the Dutch family originally described by ter Haar et al. (1982) (see 613293.0001) and the Turkish family originally reported by Maas et al. (2004) (see 613293.0002). No mutations were found in the 6 remaining FTHS probands, including the Puerto Rican boy previously described by Wallerstein et al. (1997). Iqbal et al. (2010) noted that mutations in cis-regulatory elements might have been missed in those families, and in keeping with this hypothesis, TKS4 protein was present in fibroblasts from the Puerto Rican patient, but at markedly reduced levels compared to controls. In some of the mutation-negative FTHS families, other regions of homozygosity had also been found, consistent with possible genetic heterogeneity.

In an 8-year-old Australian boy diagnosed with Borrone dermatocardioskeletal syndrome, Wilson et al. (2014) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the SH3PXD2B gene (613293.0005) that segregated with disease in the family and was not found in 534 control samples. Analysis of SH3PXD2B in the family originally described by Borrone et al. (1993) revealed homozygosity for a 12,583-bp deletion (613293.0006). Wilson et al. (2014) concluded that Borrone syndrome and FTHS represent the same disorder, and suggested that the earlier differential description of the 2 syndromes was due to phenotypic variability as well as differences in the ages at which patients were examined. In a third family diagnosed with Borrone syndrome, originally reported by van Steensel et al. (2007) and in which disease did not map to chromosome 5, Wilson et al. (2014) sequenced the SHPXD2B gene but did not identify any potential mutations, which suggested genetic heterogeneity.

Animal Model

Iqbal et al. (2010) used a gene-trap strategy to generate Sh3pxd2b (613293)-null mice and observed pronounced skeletal, eye, and cardiac abnormalities that phenocopied the majority of the defects associated with Frank-ter Haar syndrome.

Mao et al. (2011) studied the eyes of the nee strain of mice, which carry a spontaneously arising mutation in Sh3pxd2b, to determine whether the mice developed glaucoma. From an early age, nee mice uniformly exhibited severe, circumferential iridocorneal adhesions, blocking aqueous humor outflow. By 3 to 4 months of age, they exhibited high intraocular pressure (30.8 + 12.5 mm Hg), corneal opacity, and enlarged anterior chambers with progressive retinal ganglion cell loss, optic nerve head excavation, and axon loss. Thus, the eyes of nee mice exhibited anterior segment dysgenesis and early-onset glaucoma. Mao et al. (2011) concluded that because SH3PXD2B was predicted to be a podosome adaptor protein, their findings implicated podosomes in the normal development of the iridocorneal angle and the genes influencing podosomes as candidates in glaucoma. Mao et al. (2011) also postulated that because of the early-onset, high-penetrance glaucoma, nee mice offered many potential advantages as a new mouse model of glaucoma.

History

Melnick-Needles syndrome (309350) is a disorder of generalized bone dysplasia characterized by cortical irregularity and shortness and bowing of the long bones with metaphyseal flare, inherited in an X-linked dominant pattern with, usually, lethality in hemizygous males. It is caused by mutation in the filamin A gene (300017). Two of the 3 patients of ter Haar et al. (1982), in whom the clinical diagnosis was made based on skeletal and craniofacial characteristics, were male, suggesting the possibility of an autosomal recessive form. These 3 original patients had additional findings of congenital glaucoma and heart defects, which were thought to be infrequent manifestations of Melnick-Needles syndrome. Hamel et al. (1995) proposed ter Haar syndrome as distinct from Melnick-Needles syndrome; recessive inheritance, congenital glaucoma, and congenital heart disease distinguish ter Haar syndrome as a unique entity. Maas et al. (2004) suggested that this disorder be referred to as Frank-ter Haar syndrome because of the initial description by Frank et al. (1973).