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Hypotrichosis Lymphedema Telangiectasia Syndrome

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Genetics:

*Gene map locus 20q13.33

[Inheritance: autosomal dominant or autosomal recessive

Synonym: HLTS

Symptoms: 

Leg lymphedema, telangiectasis permanent dilation of preexisting small blood vessels, creating focal red lesions.),

angioma

Treatment:

There is no cure for the condition and thus, treatments would focus on the symptoms and/or complications such as lymphedema.

Pat O'Connor

May 28, 2008

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Clinical Information and Studies:

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HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA SYNDROME

OMIM ID: #607823 

Alternative titles; symbols

HLTSGene map locus 20q13.33

TEXT

A number sign (#) is used with this entry because the hypotrichosis-lymphedema-telangiectasia syndrome is caused by mutation in the transcription factor gene SOX18 (601618).

CLINICAL FEATURES

Irrthum et al. (2003) described 3 families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. In the first family, previously reported by Devriendt et al. (2002), a boy and girl, offspring of first-cousin Belgian parents, were affected. The boy was born at 32 weeks' gestation and presented with respiratory distress. A normal amount of scalp hair was present at birth but decreased progressively to the extent of total alopecia at age 6 months. The hair remained very sparse with absent eyebrows and eyelashes; sweating, nails, and teeth were normal. The skin over the hands and feet was thin and transparent, with visible blood vessels. Bilateral hydrocele was surgically corrected at age 12 years. Beginning at approximately 15 years of age, the patient progressively developed lymphedema of the legs. At 25 years of age, a doppler ultrasonogram of the venous system of the legs was normal. At that time, however, lymphatic scintigraphy with radiolabeled tracer showed no evidence of lymphatic flow from the dorsum of the foot. His younger sister presented with a similar phenotype. At birth she had normal black hair. A vascular nevus was present on the palm of the right hand and faded during childhood. During infancy, her hair diminished progressively, and from approximately 2 years of age her hair was very sparse with no eyebrows or eyelashes, and she did not develop axillary or pubic hair at puberty. Around puberty, she developed progressive lymphedema of the legs. At age 26 years she showed normal teeth, nails, and sweating, but her skin was thin. The skin over her hands and feet was transparent, and dilated veins and varicosities were apparent on the palm of her right hand. The single affected individual in the second family studied by Irrthum et al. (2003) was a 12-year-old girl, the offspring of unaffected first-cousin Turkish parents, who had previously been described in detail by Glade et al. (2001). Lymphedema of the legs appeared at age 4 years. Scalp hair had always been sparse; eyebrows and eyelashes were missing. Palms and soles showed multiple telangiectasias, with ectatic capillaries and cutis marmorata-like lividity of the skin. The index patient in the third family described by Irrthum et al. (2003), whose parents were normal and nonconsanguineous, had sparse hair at birth and presented with swelling of the upper eyelids, scrotal edema, and very large bilateral hydroceles. Hair loss began at approximately 6 months of age, accompanied by a lightening of its color. At 6 years of age, alopecia was almost complete, including eyebrows and eyelashes. The patient presented mild eczema on the cheeks and telangiectasias on the scalp, scrotum, and legs. His nails and teeth were normal. His brother died in utero at 30 weeks' gestation. The fetus had nonimmune hydrops fetalis, with chylous effusions in the pleural and peritoneal cavities. The lungs presented generalized vascular congestion and a mild dilatation of lymphatic vessels. 30 MEDLINE Neighbors

MOLECULAR GENETICS

In each of the 3 HLTS families they described, Irrthum et al. (2003) identified a mutation in the SOX18 gene. In the first and second families, both consanguineous, they identified homozygosity for the mutations ala104 to pro (A104P; 601618.0001) and trp95 to arg (W95R; 601618.0002), respectively. In the third family, which was nonconsanguineous, they identified a heterozygous cys240-to-ter mutation (C240X; 601618.0003) in the 2 affected brothers, which indicated that they had a dominant form of HLTS, apparently inherited from a parent who had the disorder in probable gonadal mosaicism. 30 MEDLINE Neighbors

REFERENCES

1. Devriendt, K.; Vikkula, M.; Irrthum, A.; Mattjijs, G.; Mertens, A.; Fryns, J.-P. :
Autosomal recessive alopecia and lymphedema. (Abstract) Genet. Counsel. 13: 74-75, 2002.
2. Glade, C.; van Steensel, M. A.; Steijlen, P. M. :
Hypotrichosis, lymphedema of the legs and acral telangiectasias--new syndrome? Europ. J. Derm. 11: 515-517, 2001.
3. Irrthum, A.; Devriendt, K.; Chitayat, D.; Matthijs, G.; Glade, C.; Steijlen, P. M.; Fryns, J.-P.; Van Steensel, M. A. M.; Vikkula, M. :
Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am. J. Hum. Genet. 72: 1470-1478, 2003.
PubMed ID : 12740761

CREATION DATE

Victor A. McKusick : 5/23/2003

EDIT HISTORY

tkritzer : 5/28/2003
tkritzer : 5/23/2003

Copyright © 1966-2004 Johns Hopkins University

http://omim.org/entry/607823

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Hypotrichosis, lymphedema of the legs and acral telangiectasias - new syndrome?

European Journal of Dermatology. Volume 11, Numéro 6, 515-7, Novembre - Décembre 2001, Article revue

Auteur(s) : C. GLADE, M. A.M. van STEENSEL, P. M. STEIJLEN, University Medical Centre Nijmegen, Dept. of Dermatology 802, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Illustrations
Summary : We describe a girl of Turkish descent suffering from a peculiar combination of symptoms. The presenting complaint was bilateral lymphedema of the legs; additional symptoms include hypotrichosis, telangiectasias and angiomata limited to acral regions. We discuss the possibility that this girl suffers from Noonan/cardio-facio-cutaneous syndrome. We conclude that the combination of symptoms listed here probably represents a new syndrome for which we propose the name hypotrichosis-lymphedema-telangiectasia syndrome.

Keywords : hypotrichosis, lymphedema, telangiectasia, syndrome.

ARTICLE

Lymphedema of the legs combined with hair abnormalities can be a prominent feature of Noonan syndrome (MIM 163950). This phenotype has previously been referred to as "male Turner syndrome" because of the similarities with Turner (45,X0) syndrome. The most prominent characteristics are short stature, webbed neck, triangular facies and sparse, sometimes woolly or fragile hair. Congenital heart disorders can also be a part of the phenotype as can the skin disorder ulerythema ophryogenes. If the latter anomalies dominate the phenotype, it is called cardio-facio-cutaneous syndrome (CFC, MIM 115150). Noonan and CFC syndrome are obviously allelic [1].

Here we describe a girl of Turkish descent suffering from a combination of symptoms that bears some resemblance to Noonan/CFC syndrome but seems sufficiently distinct to warrant description as a separate entity.

Case Report

History

The patient, a 12 year-old female, is the first child of consanguineous (first cousins) Turkish parents (Fig. 1). A younger sib is healthy. At the age of four years, swelling of the lower legs appeared. Initially, only the left leg was affected. Exercise apparently aggravated the swelling. Later, reddish papules and maculae developed on the hands and feet. The scalp hair had always been thin and did not grow well. Eyebrows had always been sparse and eyelashes had never been present.

The swelling of the legs was treated with compressive stockings, reportedly with satisfactory results. There were no other complaints and development was apparently normal. Elsewhere, a diagnosis of Klippel-Trenaunay syndrome had been made and the patient was referred to our department for further evaluation at the age of 12 years.

Physical examination

Upon examination, both lower legs appeared swollen with a puffy aspect. The swelling was due to a non-pitting oedema with moderate induration of the skin. Palpation was not painful. The palms and soles showed multiple telangiectasias that emptied when compressed and cutis marmorata-like lividity of the skin (Fig. 2). On several toes, small dark-red papular lesions resembling angiomas were seen (Fig. 3). These, too, could be emptied with compression. Some toes appeared erythematous. A receding frontal hairline was noted, with thinly implanted though normal appearing hair. Exclamation mark hairs were not seen. Eyebrows and eyelashes were missing; pubic and axillary hair growth was scant (Fig. 4). There was a slight mongoloid slant of the eyes. Nails and teeth appeared normal and physical examination did not reveal other abnormalities, particularly no cardiac murmurs, short stature, hyperkeratotic skin lesions or pigmentary abnormalities.

A paediatric evaluation revealed no abnormalities other than those described above. Skin biopsy was refused.

Discussion

The combination of lymphedema and sparse hair is found in the cardio-facio-cutaneous syndrome. This disorder, that is most likely identical to Noonan syndrome [1], is characterised by abnormal (i.e., fine and sparse) hair, hyperkeratotic skin lesions, typical face, short stature, lymphedema and cardiac defects [2]. The symptoms found in our patient show some overlap with CFC syndrome. However, cardiac defects were not found in our patient. Hyperkeratotic lesions or pigmentary abnormalities such as café au lait maculae are not present and neither are overt facial abnormalities. The growth deficiency that almost invariably occurs in CFC/Noonan syndrome [3] is absent as well. Finally, the telangiectasias, angioma-like lesions and cutis marmorata-like skin lividity involving the acral areas are not part of CFC/Noonan syndrome. Klippel-Trenaunay syndrome was considered as an explanation for the lymphedema but deemed less likely because large teleangiectatic nevi and overgrowth of limbs were lacking [4].

The hypotrichosis had been present for as long as the patient could remember. Eyelashes had never been present and the eyebrows had always been thinly implanted. The scalp hair did not grow well. There had been no episodes of accelerated hair loss. Considering this history, alopecia areata as an explanation for the hypotrichosis seems unlikely and congenital hypotrichosis a more appropriate diagnosis. The diffuse pattern and the receded frontal hair line support this notion.

The lesions on the toes bear some resemblance to lymphangiectases in the context of lymphedema. Other skin signs of lymphedema were missing, however, and the lesions were red as opposed to purple, as lymphangiectases usually are. Moreover, they could be emptied using manual pressure. For these reasons we diagnosed the lesions as angiomata.

CONCLUSION

In conclusion, we feel that the phenotype we describe here is distinct from CFC/Noonan syndrome despite having overlapping features. We propose that it is a new entity for which we propose the name hypotrichosis-lymphedema-telangiectasia syndrome.

Acknowledgements

M.A.M. van Steensel is supported by grants from the Dutch Organisation for Scientific Research (NOW grant 920-05-083) and Rebirth SA, Luxembourg.

Article accepted on 14/5/01

REFERENCES

1. Leichtman LG. Are cardio-facio-cutaneous syndrome and Noonan syndrome distinct? A case of CFC offspring of a mother with Noonan syndrome. Clin Dysmorphol 1996; 5: 61-4.

2. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz JM. New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement-the CFC syndrome. Am J Med Genet 1986; 25: 413-27.

3. Opitz JM. The Noonan syndrome. Am J Med Genet 1985; 4: 333-43.

4. Samuel M, Spitz L. Klippel-Trenaunay syndrome: clinical features, complications and management in children. Br J Surg 1995; 82: 757-61.

http://www.john-libbey-eurotext.fr/fr/revues/medecine/ejd/e-docs/00/01/86/BC/article.md?type=text.html

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Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia.

Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M.

Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and Universite catholique de Louvain, Brussels, Belgium.

Hereditary lymphedema is a developmental disorder characterized by chronic swelling of the extremities due to dysfunction of the lymphatic vessels. Two responsible genes have been identified: the vascular endothelial growth factor receptor 3 (VEGFR3) gene, implicated in congenital lymphedema, or Milroy disease, and the forkhead-related transcription factor gene FOXC2, causing lymphedema-distichiasis. We describe three families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. Using microsatellite analysis, we first excluded both VEGFR3 and FOXC2 as causative genes; we then considered the murine ragged phenotype, caused by mutations in the Sox18 transcription factor, as a likely counterpart to the human disease, because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. Two of the families were consanguineous; in affected members of these families, we identified homozygous missense mutations in the SOX18 gene, located in 20q13. The two amino acid substitutions, W95R and A104P, affect conserved residues in the first alpha helix of the DNA-binding domain of the transcription factor. In the third family, the parents were nonconsanguineous, and both the affected child and his brother, who died in utero with hydrops fetalis, showed a heterozygous nonsense mutation that truncates the SOX18 protein in its transactivation domain; this substitution was not found in genomic DNA from either parent and hence constitutes a de novo germline mutation. Thus, we show that SOX18 mutations in humans cause both recessive and dominant hypotrichosis-lymphedema-telangiectasia, suggesting that, in addition to its established role in hair and blood vessel development, the SOX18 transcription factor plays a role in the development and/or maintenance of lymphatic vessels.

PMID: 12740761 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12740761

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Vascular  defects in a mouse model of  hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation.

Aug 2009

Downes M, François M, Ferguson C, Parton RG, Koopman P.

Source

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

Abstract

Mutations in the transcription factor gene SOX18 cause vascular, lymphatic and hair follicle defects in humans with dominant and recessive forms of hypotrichosis-lymphedema-telangiectasia (HLT) syndrome. Here, we clarify the role of SOX18 in the vascular dysfunction in HLT by ultrastructural, immunofluorescence, molecular and functional analysis of vascular anomalies in embryos of the naturally occurring Sox18-mutant mouse strain ragged-opossum (Ra(Op)). Early genesis and patterning of vasculature was unimpaired in Ra(Op) embryos, but surface capillaries became enlarged from 12.5 dpc and embryos developed massive surface hemorrhage by 14.5 dpc. Large focal breaches in the endothelial barrier were observed, in addition to endothelial hyperplasia associated with impaired pericyte recruitment to the microvasculature. Expression of the genes encoding the endothelial factors MMP7, IL7R and N-cadherin was reduced in Ra(Op) embryos, suggesting that these are downstream targets of SOX18. Together, our results indicate that vascular anomalies in HLT arise from defects in regulation of genes required for the acquisition of structural integrity during microvascular maturation. 

Complete Text

http://hmg.oxfordjournals.org/content/18/15/2839.long

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