Archives ofDisease in Childhood 1995; 73: short reports 249 Trichothiodystrophy with sideroblastic anaemia Arch Dis Child: first published as 10.1136/adc.73.3.249 on 1 September 1995. Downloaded from and developmental delay Sally A Lynch, David de Berker, Alan R Lehmann, Rodney J Pollitt, Michael M Reid, William H Lamb Abstract sideroblasts. A diagnosis of sideroblastic A patient with sideroblastic anaemia, anaemia was made. His haemoglobin returned development delay, and trichothiodys- to normal after a blood transfusion and treat- trophy is presented. Trichothiodystrophy ment with pyridoxine. is a feature of several autosomal reces- Light microscopy showed pale floppy hairs sive diseases. Photosensitivity, failure to with trichorrhexis nodes and brush ends. thrive, and developmental delay are Scanning electron microscopy demonstrated commonly observed in affected cases. X loss of organised cuticular structure and ribbon linked inheritance accounts for the bulk of like morphology of the hair shaft (see fig 2). cases with sideroblastic anaemia. This Polarised light microscopy elicited the tiger tail case highlights the importance of routine appearance of alternating light and dark trans- hair microscopy in cases of atypical verse bands associated with trichothiodys- ectodermal dysplasia. trophy. Hair amino acid analysis revealed low (Arch Dis Child 1995; 73: 249-251) cystine, proline, threonine, and serine concen- trations and increased concentrations of Keywords: trichothiodystrophy, sideroblastic anaemia, transcription factor, DNA repair defect. aspartic acid, lysine, leucine, and alanine. These findings are consistent with a diagnosis of TD. Dental examination revealed only three lower Trichothiodystrophy (lTTD) is a feature of incisors with a fused left lower AB incisor. several neurocutaneous conditions. The spec- Echocardiography and a skeletal survey were trum of symptoms and signs associated with normal. TTD is extensive.1 An association between Chromosomal analysis revealed a normal sideroblastic anaemia and TTD has not been male 46,XY karyotype; in particular no abnor- reported previously. mality of XpI 1.21 was identified. Studies of cultured fibroblasts revealed no evidence of a DNA repair defect. Case report http://adc.bmj.com/ The proband was born at term weighing 2310 g (<3rd centile) to unrelated parents. Department of Human His mother was on bromocriptine for a pro- Genetics, 19/20 Claremont Place, lactinoma throughout the pregnancy. At 3 Newcastle upon Tyne months of age he was admitted to hospital NE2 4AA with failure to thrive and a heart murmur. S A Lynch The heart murmur was secondary to sidero- on September 30, 2021 by guest. Protected copyright. blastic anaemia. At 3 years of age, his weight, Royal Victoria _ _~~~~~~~~~~~~~~~~~. ..... Infirmary, Newcastle height, and head circumference were all <3rd upon Tyne, Department of centile. Hair was absent from the frontal and Dermatology temporal regions and sparse on the scalp and D de Berker eyebrows (see fig 1). He had severe dental Department of caries and a single fused lower central incisor. Haematology Nails and skin were normal. There was no M M Reid history of cutaneous photosensitivity. At age 3 his gross motor and MRC Celi Mutation social development Unit, University of were six months behind his chronological age. Sussex, Brighton Investigations, at age 3 months, had shown a AR Lehmann haemoglobin concentration of 63 g/l, with a Neonatal Screening mean corpuscular volume of 66-8 fl, and a Laboratory, The normal white blood cell count. His blood film Children's Hospital, showed marked anisocytosis, poikilocytes, Sheffield R J Pollitt stippled red cells, and occasional small nucleated red cells. Bone marrow aspirate Department of revealed a cellular marrow with erythroid Paediatrics, Bishop Auckland General hyperplasia. Dyserythropoiesis was observed Hospital with occasional binucleate red cells but no W H Lamb internuclear chromatin bridging: a feature Correspondence and reprint one would expect in congenital dyserythro- requests to: Dr Lynch. poietic anaemias. Iron staining showed that Figure 1 Photography ofcase showing sparse hair on the Accepted 17 May 1995 approximately 20% of the cells were ring scalp and eyebrows. 250 Lynch, Berker, Lehmann, Pollitt, Reid, Lamb are required for expression of all genes. It has been suggested that most of the clinical Arch Dis Child: first published as 10.1136/adc.73.3.249 on 1 September 1995. Downloaded from features of TTD result from a subtle defect in transcription caused by mutations altering TFIIH, rather than from defects in DNA repair. It is postulated that subtle deficiencies in the transcriptional apparatus have effects that are confined to specific genes, such as those involved in hair shaft development.4 Unfortunately, the biochemical pathway of hair amino acid metabolism is poorly under- stood and therefore the identities of the genes involved remain unknown. There is no Figure 2 Scanning electron microscopy ofa trichorrhexis evidence from linkage data nor from muta- node. Theflattened ribbon-like morphology ofthe hair is demonstrated. tional analysis confirming or excluding linkage to XPB, XPD, or TTDA in families with TTD and normal nucleotide excision repair. It is Discussion possible that certain mutations in XPB, XPD, The sideroblastic anaemias are a group of and TTDA cause TTD without disrupting genetic or acquired disorders characterised by DNA repair. The precise effects of a subtle the presence ofnumerous ring sideroblasts and transcriptional defect might vary significantly, severe dyserythropoieses. There is one depending on the nature of the mutation and reported case of acquired sideroblastic on the genetic background of the affected anaemia associated with bromocriptine treat- individual. This could provide an explanation ment (Committee on Safety of Medicines, for the heterogeneity of symptoms associated personal communication). There is no with TTD, and could account for the evidence to support an association between sideroblastic anaemia seen in our patient. This bromocriptine treatment in pregnancy and idea of a genetic disorder secondary to tran- sideroblastic anaemia in a child. There was scription errors is not new: the ot-thalassemia also no family history of sideroblastic anaemia mental retardation syndrome is an X linked in the family and neither parent had any condition with features of ao-thalassemia abnormalities on their blood film. X linked secondary to down regulation of the a-globin inheritance accounts for the bulk of the gene on chromosome 16.6 hereditary congenital forms of sideroblastic It is conceivable that the combination of anaemia, although autosomal dominant, TTD and sideroblastic anaemia in this boy is a recessive, and mitochondrial inheritance have complete coincidence. However, if they are been reported.2 Mutations in the erythroid related, autosomal recessive inheritance is aminolevulinic acid synthase (ALAS2) gene at likely, although there remains the possibility Xpl 1.21 have been identified in patients with that our case represents an X linked variant of http://adc.bmj.com/ pyridoxine responsive X linked sideroblastic TTD. A review of the literature revealed one anaemia.3 The boy reported here responded other case of an X linked condition in associ- well to pyridoxine, suggesting an abnormality ation with lT-D. The case report describes a in the X linked subgroup, although he had boy with TTD and atypical ornithine some atypical features. Normally, affected carbamyltransferase deficiency.7 The gene for males do not present until childhood or later. ornithine carbamyltransferase maps to Xp21.1 Patients with TTD can be broadly divided far from the ALAS2 locus at Xpl 1.21. A dele- on September 30, 2021 by guest. Protected copyright. into two main groups depending on whether or tion ofthis entire region would be easily picked not they have evidence of a DNA repair defect. up on cytogenetic analysis making the possi- As a rule, those with skin photosensitivity have bility of a contiguous gene syndrome unlikely. evidence of a DNA repair defect and those Further elucidation of the biochemical without photosensitivity do not. Defects in pathways are needed in order to determine the nucleotide excision repair can be associated presence or otherwise of an X linked enzyme with three different genetic disorders: TTD, essential for normal hair morphology. It may xeroderma pigmentosum, and Cockayne's syn- be that the clinical phenotype and laboratory drome. Complementation analysis has shown profile of genetic disorders secondary to errors that most cases within this group of TTD are in transcription are distinct from the classic allelic variants of xeroderma pigmentosum presentation. Offering prenatal diagnosis for and/or Cockayne's syndrome and that they are genetic disorders with atypical presentations genetically heterogeneous. Interestingly malig- may be hazardous as the condition may be sec- nancy, an important feature of xeroderma ondary to mutations in regulatory genes and pigmentosum, is not a feature of TTD. To not due to a mutation in the target gene. date, it is known that TTD, associated with a Further studies are ongoing in order to charac- DNA repair defect, can be caused by muta- terise the genetic basis of the condition in this tions in at least three genes, XPB, XPD, and case. TTDA.45 Recent findings have shown that the products of the XPB, XPD, and TTDA genes ,1 Itin PH, Pittelkow MR. Trichothiodystrophy: review of sul- fur-deficient brittle