Trichorhinophalangeal syndrome type 2 (ORPHA:502)
A rare multiple congenital anomalies syndrome characterized by intellectual disability, 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), limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia) and multiple cartilaginous exostoses.
Epidemiology
The prevalence is unknown. Around 100 cases were described in the literature.
Clinical description
The disease has variable severity and clinical presentation. The disorder goes along with prenatal and postnatal growth delay which can be the presenting clinical sign. Although the typical facial characteristics are present from early on, they may go unnoticed as facial morphology may differ only mildly from a typical face; thin and sparse scalp hair are also common in infants in the general population. Microcephaly is present in more than half of the affected individuals. Delayed motor and cognitive development is usually the reason for further investigations; this may lead to a decreased ability of the affected individuals to indicate joint problems of the distal limbs and hips, which are however present in a similar way as in trichorhinophalangeal syndrome (TRPS) type 1. The developmental delay vary and may be mild or marked. Multiple exostoses arise in the first five years of life, especially on the limbs but potentially also elsewhere, and become more marked with time. Exostoses may lead to bone deformation, pain, and functional problems. Malignancies are extremely uncommon.
Etiology
TRPS type 2 is caused by a microdeletion in chromosome 8q23.3-q24.11 leading to the loss of the genes TRPS1, RAD21 and EXT1 and is therefore a contiguous gene syndrome. Usually the microdeletion occurs de novo but some inherited cases have been reported. A small number of affected individuals have a deletion which involves only RAD21 and EXT1; in these patients, the facial characteristics are similar to those of Cornelia de Lange syndrome. TRPS1 is a zinc finger transcriptional repressor involved in growth regulation and the development of chondrocytes and perichondrium.
Diagnostic methods
Diagnosis is typically suspected on clinical presentation and confirmed by genetic testing through chromosomal microarray analysis.
Differential diagnosis
TRPS type 2 needs to be distinguished from other disorders in which intellectual disability and ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose. The phenotype of TRPS type 2 is very characteristic and is usually not confused with any other disorder, except for patients in whom the microdeletion does not involve TRPS1, who may resemble patients with Cornelia de Lange syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible if the pathogenic variant has previously been identified in the affected family member. Parental germline mosaicism has not been reported but remains theoretically a possibility.
Genetic counseling
The disorder is autosomal dominant. 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. Penetrance has been 100% in all reported individuals to date. Somatic mosaicism is extremely uncommon.
Management and treatment
Ectodermal manifestations and growth delay are cared for in the same way for individuals both with TRPS type 1 and TRPS type 2, and take into account the developmental level of the affected individual. In patients with a marked developmental disability, joint issues and pain need to be considered as affected individuals may be unable to indicate these by themselves. Exostoses need regular follow-up by an orthopedic specialist, and should be treated in the same way as in those with isolated multiple exostoses.
Prognosis
Life expectancy is normal. The reduced mobility and developmental problems can have a major impact on the quality of life.

                            Last update: 
                            March 2023


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


                                * European Reference Network