Short Stature, Brachydactyly, Nail Dysplasia, andMental Retardation: Further Observation of theTonoki Syndrome

Giovanni Sorge,* Sabrina Baieli, Laura Mauceri, Filippo Greco, and Agata FiumaraDepartment of Pediatric Neurology, Clinica Pediatrica dell’Universita di Catania, Catania, Italy

We studied a patient with microcephaly,short stature, type B brachydactyly, naildysplasia, skeletal anomalies, and mentalretardation. The mother of the propositushas brachydactyly of thumbs and a similarphysiognomy without mental retardation.This appears to be another observation ofthe Tonoki syndrome, a distinct autosomaldominant or X-linked clinical entity. Am. J.Med. Genet. 80:403–405, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: type B brachydactyly; coarseface; small penis; autosomaldominant inheritance; X-linked inheritance

INTRODUCTION

In 1990 Tonoki et al. reported on a new syndrome ina family in which several members had type B brachy-dactyly (short middle phalanges with short or absentterminal phalanges of fingers and toes), nail dysplasia,skeletal anomalies, dwarfism, and mental retardationas autosomal dominant or X-linked trait.

Recently we observed an affected boy and his motherwith similar manifestations. This observation confirmsthat this condition represents a distinct nosological en-tity.

CLINICAL REPORT

The propositus was a 131⁄2-year-old boy. He was thethird born of nonconsanguineous parents. He was bornat term by caesarean delivery for precocious rupture ofmembranes. His weight was 3,350 g, length 49 cm, andhead circumference (OFC) 33 cm. The mother had nohistory of febrile illness or drug intake during preg-

nancy. At age 2 months inguinal hernias were re-paired. At age 6 months he had febrile seizures. Psy-chomotor development was slightly delayed and hewalked without support at 18 months.

He was referred for mental retardation, delayedspeech, and sporadic episodes of aggressiveness. At13 1⁄2 years his weight was 35 kg (10th centile), height142 cm (10th centile), and OFC 51 cm (2nd centile)(−2 SD). The face was round, with narrow forehead,thick eyebrows, mild synophrys, upslanting palpebralfissures, large and prominent ears, thick lips (Fig. 1)and tooth decay. He also had inverted nipples, pectus

*Correspondence to: Giovanni Sorge, M.D., Clinica PediatricaUniversita di Catania, Viale Andrea Doria 6, 95125 Catania,Italy. E -mail: g.sorge@telmedia.it or sorge@mbox.unict.it

Received 4 May 1998; Accepted 21 July 1998Fig. 1. Propositus. Note thick eyebrows, mild synophrys, large ears,

and thick lips.

American Journal of Medical Genetics 80:403–405 (1998)

© 1998 Wiley-Liss, Inc.

excavatum, thoracic kyphosis, and lumbar lordosis.The hands showed brachydactyly with clinodactyly ofthe fifth fingers; mild cutaneous syndactyly was pre-sent between second and third fingers bilaterally (Fig.2A). The halluces were large, the nails of second andfourth toes on the right and of fourth and fifth on theleft were small, hypoplastic, and deep-set. The fourthtoe of the right foot overlapped the fifth (Fig 2B). Healso had a small penis. He had mild mental retardationwith a history of poor scholastic performance. Derma-toglyphic findings were three arches and seven loopspatterns, the atd angles were normal bilaterally, andthere was an hypothenar loop in the right hand.

Results of routine blood analyses were normal. Thekaryotype (GTG banding) was normal. Brain NMR wasnormal. Skeletal radiographs showed a rudimentaryextra left rib; hypoplastic distal phalanges of the sec-ond, third, and fifth fingers, and slight shortness of

fourth metacarpal bone (Fig. 3A); and hypoplastic dis-tal phalanges of the halluces (Fig. 3B). These findingsare characteristic of type B brachydactyly.

The mother has a facial appearance quite similar tothat of her son, especially for the shape of the eyebrowsand of the palpebral fissures. Moreover her thumbs areshort with slightly hypoplastic distal phalanges on X-rays (Fig. 4). The nails are normal and intelligence isalso normal. The other relatives are normal.

Fig. 2. Propositus. A: Brachydactyly of the hands and clinodactyly ofthe fifth finger. B: Big hallux; nail dysplasia of second and fourth toes onthe right and of fourth and fifth on the left; fourth right toe overlaps thefifth.

Fig. 3. Propositus. A: Hypoplastic distal phalanges and shortness offourth metacarpal bone. B: Hypoplastic distal phalanges of the halluces.

404 Sorge et al.

DISCUSSION

The clinical picture of our patient, characterized byshort stature, relative microcephaly, ‘‘coarse face’’ withsynophrys, large prominent ears, short philtrum, thicklips, tooth decay, type B brachydactyly, nail dysplasia,pectus excavatum with thoracic kyphosis and lumbarlordosis, and mild mental retardation was described byTonoki et al. [1990] in a mother and her sons.

The same author reported another new congenitalmalformation syndrome in 1988 comprisingbrachytelomesophalangy with hypoplastic toe nails,dermatoglyphic anomalies, bilateral cryptomicrotia, bi-fid scrotum and chordee without hypospadias, and nor-mal intelligence [Tonoki et al., 1988]. The patients wedescribed have similar anomalies of the hands withoutcryptomicrotia and with mental retardation in one ofthem; therefore this diagnosis can be excluded.

In the London Dysmorphology Database (LDDB)[Winter and Baraitser, 1996] the combination ofbrachydactyly, small hypoplastic deep-set nails, syn-ophrys, and mental retardation generates a list of 14syndromes, including the Tonoki syndrome (Table I).Many of these syndromes can be ruled out easily. Thesyndrome described by Fryns et al. [1977] of micro-cephaly, rudimentary distal phalanges, small nails, se-vere mental retardation, IUGR, spasticity, blindnessdue to retinal detachment, and short metacarpal andbroad proximal phalanges can be excluded. The syn-drome described by Brunoni et al. [1984] can also beexcluded because it also comprises radial aplasia andbifid thumbs. Completely different findings are presentin patients with fetal warfarin syndrome, histidinemia,Kabuki make-up syndrome, Mulvihill progeria-likesyndrome, acro-fronto-facio-nasal dysostosis, Toriellosyndrome, and the Wiedemann microcephaly-shortthumbs-MR syndrome, all conditions on the LDDB list.

Out of the remaining syndromes of the LDDB, Float-ing-Harbor syndrome can be excluded for several clini-cal reasons and mainly for the different shape of noseand columnella. For similar reasons we think that thecondition reported by Senior [1971] and characterized

by impaired growth and onychodysplasia can be ruledout.

Some phenotypic similarity with our patient is pre-sent in the syndrome described by Tsukahara et al.[1989] of brachydactyly, dwarfism, ptosis of eyelids, mi-crocephaly, and mental retardation. In fact in this casethere are type A1 brachydactyly and other signs suchas mixed deafness, hip and radial head dislocation, andmyopia, all features not recorded in the present family.

In their original report, Tonoki et al. [1990] made anexcellent differential diagnosis with other syndromesin which type B brachydactyly is present. They ex-cluded the syndromes of Sorsby, Keutel, Larsen, Berk-Tabatznik, Coffin-Siris, and Rudiger; the same obser-vations and diagnostic suggestions apply in our case.

REFERENCESBrunoni D, Lederman H, Ferrari S (1984): Mesomelic dwarfism, skeletal

abnormalities, ectodermal dysplasia. J Clin Dysmorphol 2:14–18.Fryns JP, Van den Berge H (1977): Pre- and postnatal growth retardation

with severe mental retardation, acral limbs deficiencies and ocularanomalies, a new syndrome of inherited intrauterine dwarfism? ActaPaediatr Belg 30:227–232.

Mulvihill JJ, Smith DW (1975): Another disorder with prenatal shortnessof stature and premature aging. BDOAS 11:368–371.

Richieri-Costa A, Colleto GMDD, Gollop TR (1985): A previously unde-scribed autosomal recessive multiple congenital anomalies/mental re-tardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial polydactyly. 20:631–638.

Senior B (1971): Impaired growth and onychodysplasia. Short childrenwith tiny toenails. Am J Dis Child 122:7–11.

Tonoki H, Ohura J, Niikawa N (1988): Cryptomicrotia and short, stubbyfingers with excess fingertip arch patterns in a mother and son. Am JMed Genet 29:857–862.

Tonoki H, Kishino T, Niikawa N (1990): A new syndrome of dwarfism,brachydactyly, nail dysplasia and mental retardation in sibs. Am JMed Genet 36:89–93.

Tsukahara M, Azuno Y, Kajii T (1989): New syndrome. Type A1 brachy-dactyly, dwarfism, ptosis, mixed partial hearing loss, microcephaly,and mental retardation. Am J Med Genet 33:7–9.

Wiedmann HR, Grosse KR, Dibbern H (1985): An atlas of characteristicsyndrome: a visual aid to diagnosis for clinicians and physicians. Lon-don: Wolfe Medical Publications, pp 106–107.

Winter RM, Baraitser M (1996): ‘‘London Dysmorphology Database(LDDB).’’ Windows version 1.0. Oxford: Oxford University Press, Elec-tronic Publishing.

Fig. 4. Mother. Note short thumbs with slight hypoplastic distal pha-langes.

TABLE I. LDDB Nosology

Brunoni et al., [1984]: radial aplasia, short stature, unusualface

Fetal warfarinFloating-Harbor: short stature, delayed bone age, broad noseFryns et al., [1997]: short stature, mental retardation, detached

retinaHistidinuriaKabuki syndromeMulvihill [1975]: progeria-like syndromeRichieri-Costa [1985]: acro-fronto-facio-nasal dysostosisSenior [1971]: impaired growth, onychodysplasiaSmith-Fineman-Myers: short stature, mental retardation,

unusual faceTonoki et al., [1990]: brachydactyly, nail dysplasia, mental

retardationToriello-Carey: agenesis of corpus callosum, facial anomalies,

Robin sequenceTsukahara et al., [1989]: brachydactyly, dwarfism, ptosis,

microcephaly, mental retardationWiedemann [1985]: microcephaly, short thumbs, mental

retardation

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