American Journal of Medical Genetics 46:592-596 (1993)

Oculocerebral Hypopigmentation Syndrome Associated With Bartter Syndrome C. P. White, M. Waldron, J. E. Jan, and J. E. Carter Divisions of Neurology (CS.W., J.E.J.) and Nephrology (M.W., J.E.C.), Department of Pediatrics, University of British Columbia, Vancouver, B.C., Canada

We describe a 20-year-old man with tyrosin- ase-negative oculocutaneous albinism, men- tal retardation, epilepsy, sensorineural deaf- ness, ataxia, and Bartter syndrome. When combined, these neurocutaneous and renal findings form a previously unreported combi- nation.

The neurological and cutaneous manifesta- tions of this case are distinctly different from those of the syndrome first reported by Cross et al. [19671. The literature is reviewed and an attempt is made at classifying the oculocere- bra1 hypopigmentation syndromes. 0 1993 Wiley-Liss, Inc.

KEY WORDS: Oculocutaneous albinism, at- axia, Bartter syndrome

INTRODUCTION Oculocutaneous albinism (OCA) is defined as an in-

herited hypomelanosis involving the skin, hair, and eye. It exhibits marked heterogeneity and classification is difficult. The same is true for the renal tubulopathies collectively known as Bartter “syndrome.”

There have been a number of case reports of associ- ated abnormalities in patients with OCA. These most commonly involve the nervous system. The association presented in this case, also including Bartter syndrome, is unusual and has not been reported before. Reviewing the previously reported cases of hypopigmentation and central nervous system dysfunction leads us to conclude that there are at least two distinct oculocerebral hypo- pigmentation syndromes.

CLINICAL REPORT The propositus was born at term to nonconsan-

guineous parents. The birth weight was 3,000 g and apart from prolonged labor no perinatal complications

Received for publication August 31, 1992; revision received Jan- uary 11, 1993.

Address reprint requests to Dr. C . P. White, Department of Neurology, Royal Liverpool Children’s Hospital, Eaton Road, Liv- erpool, United Kingdom, L12 2AP.

were reported. He was noted at birth to have white hair and pale translucent irides. Assessment at 4 months, following a generalised seizure, showed him also to be hypotonic, developmentally delayed, and visually inat- tentive. Investigations documented normal amino acids, organic acids, immunoglobulins, and TORCH screen. The hair bulb incubation test showed no increase in pigmentation [Kugelman and van Scott, 19611. Seizures were controlled with phenytoin.

When first seen by the Visually Impaired Program at age 5 years, he was found to have, in addition to his albinism, mental retardation and to be markedly ataxic. Audiometry showed a moderate bilateral sensorineural hearing loss.

At age 8 years, he was investigated because of epi- sodes of vomiting and dehydration, failure to thrive, and a deterioration in his mobility. Neurological findings were unchanged apart from evidence of mild proximal muscle weakness. Psychometric testing confirmed se- vere mental retardation. Metabolic changes consistent with Bartter “syndrome” were found (Table I). The pa- tient was found to have hypokalaemia and a metabolic alkalosis in the presence of a normal blood pressure. Plasma renin activity was increased. A percutaneous renal biopsy showed definite evidence of juxtaglomeru- lar hypertrophy and hyperplasia. Nerve conduction studies were normal but the EMG disclosed evidence of a myopathic process. CK was normal. The myopathy was thought to be secondary to hypokalaemia and a muscle biopsy was not performed. Administration of indometh- acin increased the serum potassium level from 2.4 to 3.1 mmol/l but, following a recurrence of generalised tonic- clonic seizures, this was discontinued. The patient was discharged on phenytoin and potassium supplements.

At age 16 years, his generalised tonic-clonic seizures recurred and he developed massive myoclonic jerks. A change to carbamazepine controlled his generalised tonic-clonic seizures but the myoclonic episodes contin- ued, unassociated with epileptiform discharges on the EEG. Repeat metabolic investigations showed persis- tent hypokalaemia and severe hypomagnesemia (Table I). Attempts to correct this with oral supplementation were not successful.

At age 20 years, he was reassessed as his muscle weakness and myoclonic jerks continued to interfere with mobility. On physical examination, height, weight

0 1993 Wiley-Liss, Inc.

Oculocutaneous Hypopigmentation Syndrome 593

TABLE I. Summary of Renal Investigation

Age (years) 9 16 20

Height (cm) 122.5 142.5 Weight (kg) 22.0 33.4 K' (mmoV1) 2.5 2.4 c1- (mm0Ul) 99 97 HCO (mmol/l) 27.5 28 Mg2+3 (mmol/l) - 0.42 Uric Acid (mmol/l) - 190 Aldosterone Supine 313 - (pmol/l) Upright 216 - Renin Supine 6.8 - (ng/Ysec) Upright 6.2 -

Urinary K' (mmolll) 97

Urinary Ca + (mmoYday) - - Urinary -

Urinary Na' (mmolll) 160 -

Urinary Mi$+ (mmoV1) - 3.5

- Prostaglandins

(ng.24 hrs)

165.2 47.7

2.7 96 30

210 0.46

- 247 -

4.48

91 4.5 0.5

pGEl 1708 PGFZ 1974

(all less than 3rd centile).

(N.R. 95-109) (N.R. 21-29)

(N.R. 235-510)

(N.R. 3.5-5.0)

(N.R. 0.75-0.95)

(N.R. 195-975)

(N.R. 0.28-1.11

(N.R.<7.5) (N.R. 350-820) (N.R. 375-800)

and head circumference were all on the 2nd centile. He had white hair and very fair skin with no naevi. There was minimal gingival hypertrophy (consistent with pre- vious phenytoin therapy) but no other dental abnormal- ities. The eyes were pale blue with translucent irides and he was markedly photophobic. Ophthalmological examination showed continuous pendular fixation nys- tagmus. He had a full range of eye movements with an alternating esotropia. His visual acuity was 41200. Fun- doscopy showed hypoplastic optic nerves and fundal hy- popigmentation. He was slightly hypotonic with mild proximal muscle weakness and marked truncal and limb ataxia. The tendon reflexes were normal. Blood pressure was 110174 mm Hg (Fig. 1).

The results of repeat renal investigations are detailed in Table I. Other investigations included a normal full blood count with no vacuolated lymphocytes or inclusion bodies. Repeat amino acids, organic acids, and immu- noglobulins were normal, as were chromosomes. A cra- nial CT scan was normal. The hair bulb incubation test showed no increased in pigmentation. Monocular flash visual evoked potentials showed evidence of asymmetry. The skin biopsy (Fig. 2) showed normal numbers of melanocytes but scarce stage I and I1 melanosomes.

Over a 3 day period, 10 g of magnesium sulphate was given by intravenous infusion. Amiloride 2.5 mg daily was started and oral magnesium oxide supplements were increased as tolerated to 750 mg daily. After 2 weeks, serum magnesium increased to 0.62 mmoYl and potassium to 4.2 mmolil. This normalisation of his bio- chemistry has been maintained and with it, his foster parents have noted a marked improvement in his gen- eral wellbeing and strength. There has also been a dra- matic decrease in the frequency and severity of his myo- clonic jerks as well as an improvement in his speech.

DISCUSSION In 1967, Cross et al. described 3 sibs in an inbred

Amish family with generalised hypopigmentation, ocu-

Fig. 1. Patient age 20 years.

594 Whiteet al.

Fig. 2. a: Age- and site-matched control skin biopsy showing basal epidermal cells and melanocyte (M) with abundant melanosomes (circled) (electron micrograph x 6,700). b Patient’s skin biopsy showing basal epidermal cells and melanocyte (M) with virtual absence of melanosomes (electron micrograph x 6,700). c: Inset showing immature melanosomes of case (electron micrograph x 32,500).

lar anomalies (microphthalmia, corneal opacities, nys- tagmus), dental abnormalities, mental retardation, spasticity, and athetosis. Since then, there have been a number of other reported cases of similar oculocerebral syndromes associated with hypopigmentation. The clin- ical findings in these cases and those of this patient are summarised in Table 11.

Classification of OCA is based on the clinical findings, inheritance pattern, the results of the hair bulb incuba- tion test, and electron microscopy of skin or hair bulb

[Witkop et al., 19711. Electron microscopy of hair bulbs by Witkop et al. 119711 from the original cases reported by Cross et al. 119671 showed reduced numbers of melanocytes containing few clustered melanosomes in all stages of development. This differs from the findings in other forms of OCA where melanocyte numbers are normal but only early stage melanosomes are present. The authors concluded that these children, although phenotypically albinos, cannot, strictly speaking, be classified as such [Witkop et al., 19831. Similar findings

Oculocutaneous Hypopigmentation Syndrome 595

TABLE 11. Summary of Neuro-opthalmological Data Available on Previously Reported Cases

Reference

Cross et and Fuchs et al. et al. et al. et al. et al. Present al. [19671 [1975] [19831 [19881 [19891 119871 [19891 Patient

Passarge Preus F‘ryns Courtens Patton Castle

Patient 1 2 3 1 1 2 1 2 1 1 1 1 M F F F M F M Sex F M M

Parental Consanguinity + + + Hypopigmentation of skin and hair + + + + + + + + + + + + Hypopigmentation of irides ? ? ? ? ? ? ? ? - Naevi + + + ? ? ? - ? + + + Mental retardation + + + + + + + + + + + + Spasticity + + + + + - + + Athetosis + + + + + ? + Ataxia Abnormal dentition ? + + + + ? - ? + ? Nystagmus + + + + + ? + ? + + + + Fundal appearance of albinism ? ? ? ? + + - - + ? + Microphthalmia + + + + Corneal anomalies + + + - Cataracts

- F -

M - - + + + + -

+ + + -

- - - - - + - - - + - + - - - - - - - _ -

- -

-

- - - ? + + + + - - +

- - - - - - - - - - -

- - - - - -

+ , present; - , absent; ? not commented on in text.

were found in the skin biopsies of the cases reported by Courtens et al. 119891 and Fryns et al. [19881.

The skin biopsy in the case of Patton et al. 119871 shows normal numbers of melanocytes but few stage 1V melanosomes. This and the clinical manifestations sug- gest that the child has tyrosinase positive OCA. Our patient would be classified as tyrosinase negative [Witkop et al., 19891. The case reported by Castle et al. [19891 has clinical manifestations and results of a hair bulb incuba- tion test compatible with tyrosinase positive OCA but unfortunately a skin biopsy was not performed. In the other cases, no comment is made about the ultrastruc- tural appearance of skin or hair bulb (Table 111).

The 3 cases described by Patton et al. [19871, Castle et al. [19891, and ourselves all appear to be true ocu- locutaneous albinos in contrast to the other cases. Their clinical manifestations are remarkably similar includ- ing the absence of additional ocular findings and spas- ticity. Patton et al. [19871 considered their case to be analogous to the two sisters described by Preus et al. [19831 and suggested that these cases represented a different condition from that described by Cross et al. [1967]. We think the oculocutaneous hypopigmentation syndromes should be subdivided and that a distinction should be made between those with and without true OCA.

TABLE 111. Summary of Investigations Available on Previously Reported Cases Report and Case Number Hair bulb incubation Skin biopsy

Cross et al. [19671 1.1 1.2 1.3

Passarge and Fuchs-Mecke [19751 2.1

3.1 3.2

4.1 4.2

5.1

Preus et al. [19831

F‘ryns et al. [19881

Courtens et al. [19891

Patton et al. [19871 6.1

Castle et al. [19891

Present case 7.1

8.1

Slight increase in pigmentation “pinion Reduced nos. of melanocytes with gear” appearance clumping of melanosomes

ND“ “Depigmented epidermis” (no EM done)

ND ND

ND ND

ND

ND ND

Patchy absence of melanocytes ND

Melanosomes in all stages but in reduced numbers

Moderate increase in pigmentation

Marked increase in pigmentation ND

No increase in pigmentation

Normal nos. of melanocytes with few stage 4 melanosomes

Normal nos. of melanocytes with stage I and I1 melanosomes only

a ND, not done.

596 White et al.

The metabolic and renal findings are consistent with a form of Bartter “syndrome” [Bartter et al., 19621. The marked magnesium wasting and hypocalcuria most closely resemble the cases first described by Gitelman et al. 119661. Bartter syndrome includes a heterogeneous group of tubulopathies with similar clinical and bio- chemical characteristics. A comprehensive review by Stein [19851 details some of the problems with precise diagnosis and classification.

The inheritance of most forms of Bartter syndrome is considered to be autosomal recessive [Pereira and Van Wersch, 19831. De Keyser et al. [19881 reported Bartter syndrome in association with trisomy 3 mosaicism, but this was thought to be a chance occurrence.

We have not found any reports describing the combi- nation of oculocutaneous hypopigmentation and Bartter syndrome. As with De Keyser et al.’s [19881 report, this case most likely represents a chance concurrence of au- tosomal recessive conditions.

ACKNOWLEDGMENTS We thank Dr. Glenn Taylor (Department of Pathology,

University of British Columbia and British Columbia’s Children’s Hospital) for his assistance in preparing and interpreting the skin biopsies.

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the juxtaglomerular complex with hyperaldosteronism and hypo- kalaemic alkalosis. Am J Med 33:811-828.

Castle DJ, Jenkins T, Shawinsky AA (1989): The oculocerebral syn- drome in association with generalised hypopigmentation. A case report. S Afr Med J 76:35-36.

Courtens W, Broeckx W, Ledoux M, Vamos E (1989): Oculocerebral

hypopigmentation syndrome (Cross syndrome) in a gipsy child. Acta Paediatr Scand 78:806-810.

Cross HE, McKusick VA, Breen W (1967): A new oculocerebral syn- drome with hypopigmentation. J Pediatr 70:398-406.

DeKeyser F, Matthys E, De Paepe A, Verschraegen-Spae MR, Matton M (1988): lkisomy 3 mosaicism in a patient with Bartter syndrome. J Med Genet 25:358.

Fryns JP, Dereymaeker AM, Heremans G, Marien J, van Hauwaert, ‘hrner G, Hockey A, van den Berghe H (1988): Oculocerebral syn- drome with hypopigmentation (Cross syndrome). Clin Genet

Gitelman HJ, Graham JB, Welt LG (1966): A new familial disorder characterised by hypokalaemia and hypomagnesemia. lkans Assoc

Kugelman TP, van Scott EJ (1967) Qrosinase activity in melanocytes of human albinos. Invest Dermatol 37:73.

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Witkop CJ, Quwedo WC, Fitzpatrick TB, King RA (1989): Albinism. In Scriver CR, Reaudet AL, Sly WS, Valle D (eds): ‘The Metabolic Basis of Inherited Disease.” 6th Edn. New York McGraw Hill pp 2905-2947.

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