Eur J Pediatr (2003) 162: 459–461 DOI 10.1007/s00431-003-1228-5
O R I GI N A L P A P E R
Margherita Silengo Æ Mariella Valenzise Marco Spada Æ Giovanni B. Ferrero Silvio Ferraris Æ Patrizia Dassi Æ Laura Jarre
Hair anomalies as a sign of mitochondrial disease
Received: 12 February 2003 / Revised: 27 February 2003 / Accepted: 19 March 2003 / Published online: 24 April 2003 Ó Springer-Verlag 2003
Abstract In 8 out of 25 children with a mitochondrial disorder, slow growing, sparse and fragile hair was observed as an early sign of their disease. Microscopic examination of the hair showed the presence of trichorrhexis nodosa and pili torti. Hair abnormalities can be added to the wide clinical spectrum of mitochondrial disorders. Conclusion: Microscopic hair examination is an easy, first level diagnostic tool that can lead to a suspected mitochondrial defect in the early stages of the disease, before symptoms of progressive multi-organ involvement develop.
years, however, it has become clear that defects of oxidative phophorylation can produce a variety of syndromic and non-syndromic disorders. A characteristic feature is the increasing number of organs and systems involved in the course of the disease [2]. Skin and hair anomalies in patients affected by mitochondrial disorders have only recently been reported [1]. We describe hair changes in 8 out of 25 children affected by different oxidative phosphorylation defects. Their presence should lead the physician to suspect a mitochondrial disease, when other unrelated symptoms are observed.
Keywords Hair abnormalities Æ Mitochondrial disease Æ Pili torti Æ Trichorrhexis nodosa
Subjects and methods Subjects
Introduction A mitochondrial disease, caused by a defect of oxidative phosphorylation, can be suspected in patients presenting with an unexplained combination of neurological and non-neurological symptoms. The diagnosis is difficult when the first symptom is observed but it becomes easier when two or more unrelated features develop. Neurological and muscular presentation is common due to the fact that both brain and muscle are highly dependent on the mitochondrial energy supply. In recent
A total of 25 children with mitochondrial diseases have been studied in our departments during the last 7 years. All of them had developed progressive symptoms involving different and unrelated organs. Clinical findings and metabolic screening suggested the possibility of an oxidative defect and performing mitochondrial enzymes studies on muscular biopsies (Table 1). In 8 of the 25 patients we found slow growing, sparse, thin and fragile hair. The hair of those patients, which was abnormal on clinical examination, was studied by light microscopy and by scanning electron microscopy.
Enzyme studies M. Silengo (&) Æ M. Valenzise Æ M. Spada G. B. Ferrero Æ S. Ferraris I Divisione di Clinica Pediatrica, Universita’ di Torino, Piazza Polonia 94, 10126 Torino, Italy E-mail:
[email protected] Tel.: +39-011-3135689 Fax: +39-011-677082
Open and needle biopsies of the quadriceps muscle were obtained under general or local anaesthesia and processed for histo-enzymatic and biochemical analyses of the mitochondrial respiratory chain. Mitochondrial DNA analysis, performed in one patient, showed mtDNA depletion.
P. Dassi Scuola di Specializzazione in Neuropsichiatria Infantile, Universita’ di Torino, Torino, Italy
Results
L. Jarre Neuropsichiatria Infantile, ASL 2, Ospedale Martini, Torino, Italy
Of the 25 children, 8 had hair abnormalites. No skin manifestations such as rashes, pigmentation disorders, hypertrichosis and acrocyanosis were observed. Clinical
460 Table 1 Clinical manifestations of the patients. ( EM electron microscopy, LM light microscopy) Neurological manifestations
Extraneurological sign
Hair abnormalities
Seizures, hypotonia, cerebellar hypoplasia on MRI (birth) Seizures (10 months)
Atrial septal defect (birth)
Sparse, slow growing, brittle hair (2 months) Trichorrhexis nodosa (LM) Thin hair, pilitorti (LM) (10 months)
Hypotonia (birth) Mental retardation
Chronic diarrhoea, recurrent infectious disease, failure to thrive (10 months) Hypertrophic cardiomyopathy (32 weeks of gestation and newborn period) Hypothyroidism, retinitis pigmentosa, acanthosis nigricans, obesity, tubulopathy, cardiomyopathy (10 years)
Hypotonia, encephalomyopathy (1 month), dystonia Encephalomyopathy, seizures (newborn), Ohtahara syndrome Hypotonia, psychomotor retardation, epilepsy, hearing loss (6 months) Hypotonia, mental retardation, seizures
Supravalvular aortic stenosis
Fine, sparse hair (1 month), pili torti, trichorrhexis nodosa (EM, LM) Coarse, brittle hair trichorrhexis nodosa (LM) first seen at age 10 years Sparse, woolly hair (1 month), pili torti, trichorrhexis nodosa (LM) Sparse, fine, depigmented hair, pili torti and trichorrhexis nodosa (LM) at birth Sparse, slow growing hair, trichorrhexis nodosa (LM) (6 months) Sparse, fine hair (11 months), pili torti (LM)
details of these patients are summarised in Table 1. Three cases were born to first cousins parents (patients 1, 2, 4) and all the other cases were sporadic with a negative family history. Hair abnormalities Macroscopically the hair was sparse, thin and dry. No areas of true alopecia were present. On light microscopy, trichorrhexis nodosa was observed in three of the eight patients (Fig. 1). Pili torti were the only microscopic feature in two cases, whereas trichorrhexis nodosa and pili torti were observed in three patients on both light and scanning electron microscopy (Fig. 2). The microscopic changes were present in about 10% of the hair examined and they were consistently observed in samples taken from different scalp areas. None of the patients had the ‘‘tiger tail’’ pattern of hair seen with polarised light, or the linear fractures (trichoschisis) usually observed in sulphur-deficient hair of the trichothiodystrophies.
Fig. 1 Trichorrhexis nodosa on light microscopy observed in patient 1 (left upper quadrant), patient 4 (right upper side), patient 7 (lower part of the picture)
Discussion Metabolic screening Plasma lactate levels were abnormally high in all eight cases with a high lactate/pyruvate ratio (>20) under both fasted and fed conditions. Serum copper, caeruloplasmin, zinc and folate levels were normal as were aminoacids in blood and urine and the blood biotinidase activity. Enzyme assays Spectrometric analysis of mitochondrial respiratory enzymes demonstrated the presence of isolated or generalised complex deficiencies in all eight patients (Table 2).
Clinical manifestations of mitochondrial disorders are extremely heterogeneous. Neuromuscular symptoms predominate but virtually all other tissues or organs may be involved. Skin and hair manifestations in mitochondrial disorders were first mentioned by Rotig et al. [3] and further studied recently by Bodemer et al. [1]. The latter authors did not find a distinguishing metabolic pattern in children with dermatological symptoms as compared with those without. Alopecia and hair shaft abnormalities (trichoschisis, pili torti, trichorrhexis nodosa) were observed in 6 of the 14 cases with skin disorders. They suggested that defective cellular energy supply, related to
461 Fig. 2 Sparse, light and thin scalp hair of patient 3 at 1 month of age. Pili torti on scanning electron microscopy in the right upper quadrant. Trichorrhexis nodosa on light microscopy (left lower quadrant) and on scanning electron microscopy (right lower quadrant)
mt DNA analysis
There is evidence that macroscopic and microscopic hair abnormalities are clinical markers of different types of metabolic derangement. Mitochondrial diseases are difficult to diagnose in early stages when only one symptom is present. Hair anomalies might be a presenting sign that can offer a clue to the diagnosis.
mt DNA depletion
Acknowledgements We thank Prof. M. Zeviani of the Besta Neurological Institute in Milano for the mitochondrial enzyme and DNA studies of our patients. We also thank the Anatomy Institute of Turin University for the scanning electron microscopic analysis of the hair.
Table 2 Enzymological studies of the respiratory chain of eight patients with mitochondrial disease Patient
Respiratory chain analysis
1 2 3 4 5 6 7 8
Complex Complex Complex Complex Complex Complex Complex Complex
I +IV deficiency II+III deficiency I deficiency I deficiency I +IV deficiency V deficiency I+III+ IV deficiency V deficiency
the mitochondrial defect, might explain the pathological hair growth and development. None of our cases had the skin manifestations described in the former papers. In our patients the hair was abnormally fine, sparse and slow growing. Shaft anomalies such as trichorrhexis nodosa and pili torti were seen on light and scanning microscopy. The changes are similar to those present in other metabolic disorders like Menkes/occipital horn syndrome, biotinidase deficiency and argininosuccinic aciduria. In those diseases, hair anomalies are associated with specific metabolic defects that produce in turn defective cross-linking of the keratin (Menkes/occipital horn syndrome), biotin deprivation (biotinidase deficiency) and accumulation of toxic metabolites (argininosuccinic aciduria) [4]. We have recently observed similar hair changes in three patients affected by congenital disorders of glycosylation [5].
References 1. Bodemer C, Rotig A, Rustin P, Cormier V, Niaudet P, Saudubray JM, Rabier D, Munnich A, de Prost Y (1999) Hair and skin disorders as signs of mitochondrial disease. Pediatrics 103: 428– 433 2. Munnich A, Rustin P (2001) Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet (Semin Med Genet) 106: 4—17 3. Rotig A, Bessis JL, Romero N, Cormier V, Saudubray JM, Narcy P, Lenoir G (1992) Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus and cerebellar ataxia. Am J Hum Genet 50: 364–370 4. Silengo M, Valenzise M, Sorasio L, Ferrero GB (2002) The hair as a diagnostic tool in dysmorphology. Clin Genet 62: 270–272 5. Silengo M, Valenzise M, Pagliardini S, Spada M (2003) Hair changes in congenital disorders of glycosylation. Eur J Pediatr 162: 114–115
