Trichorhinophalangeal syndrome type 1 (ORPHA:77258)
A rare multiple congenital anomalies syndrome characterized by short stature, sparse and depigmented scalp hair, typical facial characteristics (broad eyebrows, especially the medial portion, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears), and limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia).
Epidemiology
The exact prevalence is unknown. Around 250 cases have been published in the world literature. The disease is infrequently described as mildly affected individuals may go unnoticed.
Clinical description
The disease has variable severity and clinical presentation, even between family members. It presents typically with prenatal and postnatal growth delay. The facial characteristics (broad eyebrows, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears) may be noticeable early on but may also remain completely unnoticed, especially as some features such as thin and sparse scalp hair are also common in infants in the general population. As time passes, growth delay, accompanied by increasing hair loss and dental overcrowding, may make the facial features more apparent. The brachydactyly also becomes more visible. Fingers start to deviate due to epiphyseal abnormalities in childhood which continues till adulthood. Increased and/or decreased mobility in the finger joints can occur and may cause pain. Hips abnormalities and associated pain are very common; they may present sometimes in late childhood but almost invariably in adulthood. Radiology typically reveals joint dysplasia, reduced joint space and sclerotic bone. Distal limb mobility problems often develop at a later age. Hip problems can be so severe that hip replacement may be indicated in early adulthood. The term "trichorhinophalangeal syndrome type 3'' has previously been used to refer to a severe form of type 1 with pronounced facial characteristics, short stature and brachydactyly.
Etiology
TRP type 1 is caused by heterozygous pathogenic variants in TRPS1 (8q23.3). Infrequently, inversions and balanced translocation disrupting the function of TRPS1 have been reported. Pathogenic variants are considerably different in type and location, with no clear genotype-phenotype correlation. TRPS1 is a zinc finger transcriptional repressor involved in regulating growth and development of chondrocytes and perichondrium.
Diagnostic methods
Diagnosis is typically suspected on clinical presentation and confirmed by genetic testing with sequencing technology.
Differential diagnosis
The differential diagnosis includes other disorders in which ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose such as oculodentodigital dysplasia, cartilage-hair hypoplasia, and Ellis-Van Creveld syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Families should be aware that intra-familial variety in severity can be marked, and the severity of the phenotype cannot be predicted by prenatal testing.
Genetic counseling
The disorder is autosomal dominant with full penetrance. Whilst most cases occur sporadically, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Germline mosaicism has been detected in rare cases.
Management and treatment
The management and treatment are mostly supportive. Ectodermal manifestations of hair, nails and teeth can be managed with esthetic care such as the use of wigs, artificial nails, and extraction of supernumerary teeth. In patients whose growth hormone stimulation tests results are subnornal or abnormal, growth hormone therapy can be considered and may (variably) result in increased growth in height. Physiotherapy and occupational therapy can be beneficial for problems of altered distal limb mobility. Regular simple analgesics (such as NSAID) may be used to treat joint pain. Prosthetic hip implantation should be considered in individuals with severe hip dysplasia, even in early adulthood. If osteopenia is present, bisphosphonates may be considered.
Prognosis
Life expectancy is normal. The unusual facial morphology and ectodermal manifestations, combined with the reduced mobility, can have a marked impact on the quality of life. Peer support and counseling by a social scientist can be beneficial.

                            Last update: 
                            March 2023


                            - Expert reviewer(s): 
                            Pr Raoul HENNEKAM | ITHACA* - Dr S.M. [Saskia] MAAS | ITHACA*


                                * European Reference Network