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Trichorhinophalangeal Syndrome, Type II (Langer-Giedion Syndrome)

  • Author(s): Shin, Helen T
  • Chang, Mary Wu
  • et al.
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Trichorhinophalangeal Syndrome, Type II (Langer-Giedion Syndrome)
Helen T Shin and Mary Wu Chang
Dermatology Online Journal 7(2): 8

The Ronald O. Perelman Department of Dermatology, New York University Medical Center, New York, New York

Abstract

Trichorhinophalangeal syndrome (TRPS) is characterized by its unique facial features and skeletal abnormalities. A bulbous, pear-shaped nose, elongated philtrum, sparse hair, cone-shaped epiphyses and mild growth retardation are found in both type I (TRPSI) and type II (TRPSII). TRPSII can be distinguished from TRPSI when multiple exostoses or redundant skin are present. While TRPSI is inherited in an autosomal dominant fashion, most cases of TRPSII are sporadic although there are a few cases which are familial. The following is a case report of TRPSII with incomplete penetrance in the index case and exostoses and growth retardation in the patient¹s two siblings.



Case Report


Figure 1Figure 2
Trichorhinophalangeal syndrome, type II. Note the sparseness of hair, low set ears with flattened helices, bulbous nose, elongated philtrum, thin upper lip and micrognathia.

A 14 year old female presented to the pediatric dermatology clinic with dysmorphic features and skeletal anomalies. She was born at 35 weeks gestation with a birthweight of 2358 grams, with dysmorphic features noted at birth. Radiographic studies of the hands at one month of age showed lateral subluxation at the metacarpophalangeal joints of the fourth and fifth digits with markedly delayed bone age. She had a history of growth and developmental delay and several dislocated joints for which she had received multiple orthopedic interventions. In addition, she had a conductive hearing loss. Corrective surgeries included bilateral ptosis repair, jaw advancement, chin implant and club foot repair.Chromosomal analysis revealed a fragile site on chromosome 8. Her parents were nonconsanginous and her sister and half brother had multiple asymptomatic exostoses and short stature.


Figure 3Figure 4
Lateral deviation of second, fourth and fifth fingers of the right hand and the fifth finger of the left hand.

On physical examination, she was less than the 5th percentile for her age-adjusted averages of height and weight. She had colobomata of the irises, low set ears with flattened helices, a pear-shaped nose, sparse hair, an elongated philtrum, thin upper lip, supernumerary teeth, a high arched palate, micrognathia and somewhat bushy eyebrows {Fig 1, Fig 2}. She was also noted to have a left equino-varus, a dimple at the mid shaft of the right tibia, four toes on each foot and slight subluxation of the second, fourth and fifth proximal joints of the right hand and the fifth proximal joint of the left hand {Fig 3, Fig 4}. There were no exostoses.


Discussion


Trichorhinophalangeal Syndrome, type II (Langer-Giedion syndrome)

Both TRPS, types I and II are characterized by craniofacial and skeletal abnormalities such as sparse scalp hair, bulbous nose, long flat philtrum, thin upper vermilion border, short stature and cone-shaped epiphyses.[1] A contiguous gene syndrome results when mutations, usually deletions, occur in two or more genes that map next to each other on a chromasome. TRPS I is inherited in an autosomal dominant pattern and penetrance is variable. Most reported cases of TRPS II are sporadic but an autosomal dominant mode of inheritance has been suggested by occasional familial reports.[2,3] Multiple cartilaginous exostoses distinguishes TRPS II from TRPS I. They increase in number and size until skeletal maturation.[1] These exostoses mainly involve the ends of long bones and may cause pain, functional problems or deformities.[4] The exostoses and cone-shaped epiphyses of the hands and feet present within the first 5 years of life. Mental retardation with or without microcephaly, bushy eyebrows and redundant skin are other features found more frequently in TRPS II in comparison to TRPS I. Patients with redundancy or looseness of skin may be misdiagnosed in infancy as having the Ehlers-Danlos syndrome. In addition to our report, there is one other report of a conductive hearing loss in TRPS II.[5]

TRPSII is a true contiguous gene deletion syndrome in which affected individuals have deletions in both the TRPS and EXT1 genes. Patients with TRPI have a deletion only in the TRPS gene which is more centromeric on the long arm of chromosome 8. In TRPS II, there is a deletion in the EXT1 gene which is more telomeric and localized to the 8q24.11-8q24.13 region.[6] When larger pieces of 8q are deleted, mental retardation is more commonly associated with TRPSII.[6]

Exostoses in TRPS are the result of the effects of the mutations of the EXT1 gene on enchondral bone growth. EXT1 gene is thought to be a tumor suppressor gene.[7] Multiple cartilaginous exostoses also occur independently of TRPS II as an autosomal dominant disease. There are at least two other loci, EXT2 locus on chromosome 11p11-p12 and the EXT3 locus on chromosome 19p11-p13 that are known to cause multiple exostoses.[8,9] If there is nerve impingement, joint mobility problems or extreme discomfort, the exostoses may be surgically removed. The absence of exostoses in this patient and its presence in both the sister and half brother probably represent incomplete penetrance. Clinical appearance of the digits is very characteristic for cone shaped epiphyses. However, radiographic studies of the hands were only done at one month of age, at a time when radiographs often fail to detect early changes. Unfortunately, the family refused further radiologic or genetic work-up on any of the family members.

Early recognition of TRPS II is important for patients and their families in order to receive genetic counseling and other interventions addressing growth, learning, auditory, orthopedic and cosmetic issues.

References

1. Langer LO, Krassikoff N, Laxova R, Scheer-Willaims M, Lutter LD, Gorlin RJ, Jennings CG, Day DW. The tricho-rhinophalangeal syndrome with exostoses (or Langer-Giedion syndrome): four additional patients without mental retardation and review of the literature. Am J Med Genet 1994;19:81-111.

2. Murachi S, Nogami H, Oki T, Ogino T. Familial tricho-rhino-phalangeal syndrome Type II. Clin Genet 1981;19(3):149-55. PubMed

3. Shabtai F, Sandowski U, Nissimov R, Klar D, Halbrecht I. Familial syndrome with some features of the Langer-Giedion syndrome, and paracentric inversion of chromosome 8, inv 8 (q11.23----q21.1). Clin Genet 1985;27(6):600-5. PubMed

4. Bauermeister S, Letts M. The orthopaedic manifestations of the Langer-Giedion syndrome. Orthop Rev 1992;21(1):31-5. PubMed

5. Vantrappen G, Feenstra L, Frijns JP. Conductive hearing loss in the tricho-rhino-phalangeal syndrome (TRP II) or in the Langer-Giedion syndrome. Am J Med Genet 1997;72(3):372-3. PubMed

6. Ludecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willems PJ, Haan EA, Frydman M, Hamers GJ, Wells DE, et al.. Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Mol Genet 1995;4(1):31-6. PubMed

7. Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet 1995;11(2):137-43. PubMed

8. Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, van den Ouweland AMW, Raskind WH, Hofstede FC, Reyniers E, Wells DE, de Vries B, Conrad EU, Hill A, Zalatayev D, Weissenbach J, Wagner MJ, Bakker E, Halley DFF, Willems PF. Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Amer J Hum Genet 1995;57:382-387.

9. Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 1994;3(5):717-22. PubMed

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