Frank-Ter Haar syndrome (FTHS)

What is Frank-Ter Haar syndrome (FTHS)?

This rare disease is a genetic syndrome, with less than 30 cases diagnosed globally to date.

The syndrome presents with a wide range of possible symptoms that affect multiple parts of the body.

These include a number of unique facial features and potential health conditions.

This syndrome is also known as:
Dermato - cardio - skeletal syndrome Frank-ter Haar syndrome Melnick-needles Syndrome, Autosomal Recessive, Formerly Ter Haar Syndrome

What gene changes cause Frank-Ter Haar syndrome (FTHS)?

Mutations to the SH3PXD2B gene cause the syndrome. It is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Frank-Ter Haar syndrome (FTHS)?

The main physical symptoms of the syndrome include skeletal abnormalities, short digits (fingers and toes), a flattened back of the head, large cornea, wide fontanelles, a prominent forehead, widely spaced and deep set eyes, prominent eyes, full cheeks and a small chin.

Other unique facial features include a deep nasal bridge, full lips and a broad mouth.

Individuals may also be born with heart defects and be diagnosed with developmental delay

Possible clinical traits/features:
Bowing of the long bones, Flared metaphysis, Cortical irregularity, Malformation of the heart and great vessels, Dental malocclusion, Delayed cranial suture closure, Proptosis, Short long bone, Micrognathia, Abnormally large globe, Glaucoma, Full cheeks, Hypertelorism, Anterior concavity of thoracic vertebrae

How does someone get tested for Frank-Ter Haar syndrome (FTHS)?

The initial testing for Frank-Ter Haar syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Frank-Ter Haar syndrome (FTHS)

Ter Haar et al., (1982) reported two boys and a girl from an inbred pedigree with a condition resembling Melnick-Needles syndrome, but with clear differences. One case had signs of increased intraocular pressure at birth. All the cases had prominent eyes, hypertelorism, micrognathia, brachycephaly and large anterior fontanelles. Radiographs revealed metaphyseal flaring of the long bones, bowing of the tibiae and radii, and irregularly contoured ribs with multiple constrictions and flaring of the anterior ends. The vertebrae had a decreased anteroposterior diameter and anterior scalloping. There was also brachydactyly with shortening of the phalanges. Two children had congenital heart defects (double outlet right ventricle, PDA, VSD). Development was said to be normal. Hamel et al., (1992) (3rd European Dysmorphology Conference) reported a further case from the same extended pedigree who was noted to have almost absent elastin on skin biopsy. They pointed out the similarity to the case with macrocornea reported by Frank et al., (1973) (see megalocornea-skeletal anomalies), but in that syndrome the cases are retarded and do not have increased intraocular pressure. The same case was reported in more detail by Hamel et al., (1995). Further similarities with the patient reported by Billette de Villemeur et al., (1992) as a case of Bowen syndrome were also commented on.

Borrone et al., (1993) reported two brothers with a condition resembling a storage disorder, but where no biochemical defect was found. There was progressive thickening of the skin from infancy with coarsening of the face, gingival hypertrophy and severe acne. There was brachydactyly and camptodactyly and radiographs revealed reduced AP diameters of the vertebrae with some anterior beaking and appearances resembling Scheuermann disease. In the hands there was diffuse osteoporosis with undermodelling of the metacarpals and phalanges, and a suggestion of proximal tapering of the metacarpals. There were similar appearances in the feet with some areas of sclerosis. Skin biopsy showed diffuse dermal fibrosis, hyalinosis, and metaplastic ossification. Involvement of the cardiac valves was an important complication and one brother died from heart failure secondary to mitral valve prolapse at the age of 24 years.
Two Dutch brothers with this condition were described. They were facially strikingly similar (coarse facial features, prominent jaws and full upper lips) and had progressive mitral valve disease. Gum hypertrophy and osteolysis were not present, although they were younger than the Borrone et al., (1993) patients.
Megarbane et al., (1997) reported two affected sibs, the offspring of first cousin parents and also discuss overlap with Bowen syndrome.
Rosser et al., (1996) reported two brothers and a sister who had features of the condition. One brother had an XXY carrier type. In the other the karyotype was not carried out. One case had a convincing serpentine fibula. The overlap between serpentine fibula syndrome, ter Haar syndrome and Hajdu-Cheney syndrome was noted. Both males died in the first year of life from respiratory failure. Two cases had intestinal malrotation. One case had an iris coloboma.
The brother and sister, reported as having a new syndrome by Huq et al (1997), have many similarities to this condition. Camptodactyly of the second to the fourth fingers was noted with an extended index finger (giving the authors to suggest Pointer syndrome as a suitable name for the condition). Facial and radiological syndromes were similar to those seen in the ter Haar et al., (1982) patients. However there was osteoporosis and a tendency to fractures.
Wallerstein et al., (1997) reported a 13 year old boy with this condition. He had a verbal IQ of 75, performance IQ of 67 and a full scale IQ of 68.
Al-Gazali et al., (1999) reported an infant with some features of this condition. There was marked hypocalvaria with Wormian bones and clouding of the cornea was not remarked upon.
Nishimura and Nagai et al., (1998) reported a 3-year-old girl with some features of the condition, but evidence of a mosaic problem. There was short stature, congenital heart defects (ASD, VSD, PDA) and facial dysmorphism with hypertelorism, some frontal bossing, proptosis and a long philtrum. There was linear hypopigmentation on the legs. Radiological features were somewhat similar to those seen in ter Haar syndrome.
Three Turkish sibs (plus a single case) with this condition were reported by Maas et al., (2004). These authors stress that to the brachycephaly, prominent forehead and eyes, should be added the prominent, anteverted, simple ears as part of the facial gestalt.
Homozygotic mapping in 12 families has located mutations in the gene (SH3PXD2B) on chromosome 5q35.1 (Iqbal et al., 2010). The gene encodes the TKS4 protein, a podosome adaptor protein.
Three sibs were reported by Bendon et al., (2013). Two had non-scaphocephalic sagittal synostosis with raised intracranial pressure.
Wilson et al., (2014) found mutations in SH3PXD2B.
Parker et al (2014), described three patients with Frank-Ter-Haar syndrome, focusing on the dental features. The patients, 2 males and one female showed gingival hyperplasia, delayed dental development with delayed eruption, impacted teeth, increased gonial angle and accentuated gonial notch, flattened condylar head and, taurodont teeth. The patients showed typical features including brachycephaly, wide fontanelles, prominent forehead, hypertelorism, prominent eyes with macrocornea (with or without glaucoma), full cheeks,small chin, bowing of the long bones and flexion deformities of the fingers. Additional features included mucosal polyps, regurgitation of aortic and mitral valves, cardiomyopathy, unilateral hearing loss and craniosynostosis.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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