X-Linked Mental Retardation Syndrome With ShortStature, Small Hands and Feet, Seizures, CleftPalate, and Glaucoma Is Linked to Xq28

Kim Armfield,1 Retecher Nelson,2 Herbert A. Lubs,3 Bernhard Hane,2 Richard J. Schroer,2Fernando Arena,3 Charles E. Schwartz,2* and Roger E. Stevenson2

1Medical Genetics, Scottish Rite Children’s Medical Center, Atlanta, Georgia2J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina3Department of Pediatrics/Division of Genetics, University of Miami, Miami, Florida

Of the gene-rich regions of the human ge-nome, Xq28 is the most densely mapped. Mu-tations of genes in this band are responsiblefor 10 syndromal forms of mental retarda-tion and 5 nonsyndromal forms. Clinicaland molecular studies reported here add anadditional syndromic form of X-linked men-tal retardation (XLMR) to this region. Thecondition comprises short stature, smallhands and feet, seizures, cleft palate, andglaucoma. One affected male died at age 19years in status epilepticus, but others havesurvived to old age. Carrier females do nothave somatic anomalies or mental impair-ment. The gene is localized to the terminal 8Mb of Xq28 with markers distal to DXS8011showing linkage to the disorder with a lodscore of 2.11 at zero recombination. Am. J.Med. Genet. 85:236–242, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: X-linked mental retardation(XLMR); short stature; glau-coma; seizures; X chromo-some (Xq28)

INTRODUCTION

Syndromal forms of X-linked mental retardation(XLMR) have been localized to numerous regions of theX chromosome [Lubs et al., 1996]. Most of these enti-ties were defined initially by a more or less distinctive

pattern of clinical findings. Molecular studies havebrought a new dimension to the definition by allowingregional localizations and, in a few cases, identifica-tion, of the causative genes. These techniques have pro-vided the means to separate clinically similar condi-tions such as Coffin-Lowry and a-thalassemia-mentalretardation syndromes [Gibbons et al., 1995; Trevier etal., 1996] and to establish the allelic basis for clinicallydissimilar entities such as X-linked hydrocephaly andMASA syndromes [Jouet et al., 1994].

Most XLMR entities are syndromic. Fragile X syn-drome associated with expansion of the CGG trinucleo-tide repeat in the FMR1 gene appears to be the mostcommon, estimated to account for 30–40% of XLMRand 2–11% of mental retardation (MR) in males [Sher-man, 1996]. As of the Eighth International Workshopon Fragile X and X-Linked Mental Retardation, therewere 123 recognized syndromal forms of XLMR. In ad-dition, 60 families with nonsyndromal XLMR distrib-uted into at least 10 exclusive linkage groups havebeen reported [Lubs et al., 1999].

Here, we report clinical findings and linkage analy-sis of an apparently new syndromal form of XLMR.Affected males have short stature, small hands andfeet, seizures, and adult-onset glaucoma. Cleft palatewas present in two of six affected males. Linkage tomarkers in Xq28 is demonstrated.

MATERIALS AND METHODS

The partial pedigree of family K8100 demonstratedsegregation of mental retardation from four carrier fe-males to six affected males in three generations (Fig.1). An X-linked recessive pattern of inheritance wassuggested by the presence of MR in males, absence ofmanifestations in females, and absence of male-to-maletransmission. The family was ascertained through in-dividual IV-1, now age 7 years, who presented in in-fancy with multiple minor anomalies and cleft of theposterior palate. All living affected males underwentexamination according to the clinical data set forXLMR families described by Schwartz [1993]. One af-

Contract grant sponsor: National Institutes of Health; Contractgrant number: R01 HD26202; Contract grant sponsor: SouthCarolina Department of Disabilities and Special Needs.

*Correspondence to: Charles E. Schwartz, Ph.D., J.C. Self Re-search Institute of Human Genetics, Greenwood Genetic Center,One Gregor Mendel Circle, Greenwood, SC 29646. E-mail:schwartz@ggc.org

Received 15 February 1998; Accepted 23 February 1999

American Journal of Medical Genetics 85:236–242 (1999)

© 1999 Wiley-Liss, Inc.

fected male (III-6) is deceased, having died of compli-cations of status epilepticus at age 19 years. Medicalrecords and photographs of this individual were avail-able for review.

Blood was collected from 16 relatives with informedconsent. Genomic DNA was isolated from peripheralblood using a high-salt precipitation method [Schwartzet al., 1990]. Purified DNA was diluted to a concentra-tion of 105 mg/ml and stored at 4°C in TE (10 mMTris-Cl, pH 7.6, 1 mM EDTA).

The conditions used to generate the specific di-, tri-, ortetranucleotide polymorphisms were obtained throughthe Genome Database (http://gdbwww.gdb.org) [Gyapayet al., 1994]. The forward primers for the microsatellitemarkers were synthesized with fluorescein amidite(FluorePrime, Pharmacia, Uppsala, Sweden) and de-salted through Sephadex G-25 (NAP-10 columns, Phar-macia). Polymorphisms were detected using the Auto-mated Laser Fluorescent Sequencer (A.L.F., Pharmacia)and its Fragment Manager and Automated Linkage Pre-processor software [Mansfield et al., 1994].

Two-point disease-to-marker analysis was conductedusing the program, MLINK of the LINKAGE package[Lathrop and Lalouel, 1984]. The mutation rate andgene frequency were set at 3 × 106 and 0.0001, respec-tively.

RESULTSClinical Findings

Moderate to severe mental retardation was presentin all affected males. There was a history of seizuredisorder in infancy and/or early childhood in all af-fected males. Clinical findings and selected measure-ments are given in Table I. Carrier females had noabnormal findings or intellectual impairment.

The propositus, IV-1, was born at term following apregnancy complicated by preterm labor, vaginalbleeding, and abruption at 24 weeks of gestation. Birthweight was 3.2 kg, length 47 cm, and head circumfer-ence (OFC) 36.2 cm. Because of a mucous plug, he re-quired intubation and ventilation for the first 12 hoursof life. He was macrocephalic with broad forehead, wideanterior fontanelle, depressed nasal bridge, bilateralepicanthus, down-slanted palpebral fissures, a bow-shaped appearance to the mouth, cleft of the posteriorpalate, and microretrognathia. Capillary hemangio-mas were present over the nasal bridge and upper eye-lids. Patent ductus arteriosus and a small atrial septaldefect were present and have subsequently closed.

High-resolution chromosome analysis, fragile siteanalysis, and molecular analysis of FMR1 were nor-mal. Urine metabolic screen showed galactosuria, ami-

Fig. 1. Partial pedigree of Kindred 8100 with haplotype for markers in Xq28. Boxed haplotype indicates portion of “at risk” chromosome present inan individual.

XLMR Syndrome Maps to Xq28 237

noaciduria, oligosacchariduria, and organic aciduria.Follow-up studies for galactosemia and lysosomal stor-age disorders were negative. Very long chain fatty ac-ids were borderline elevated in plasma and fibroblasts;plasma pipecolic acid, erythrocyte plasmalogen, and fi-broblast phytanic acid oxidase were normal. Mutationscreening of seven exons of the proteolipid gene forPelizaeus-Merzbacher disease was negative. Cranialcomputed tomography at age 5 months showed bifron-tal subdural effusions. More recently, magnetic reso-nance imaging of the brain documented sulcal promi-nence consistent with mild cerebral atrophy.

At age 13 months he had repair of the cleft palate. Hesubsequently underwent hyoid advancement with ad-enoidectomy and tongue advancement for obstructive

and central sleep apnea. He experienced a generalizedseizure associated with fever at age 6 months andagain at age 3 years. He has undergone surgery forstrabismus.

At 7 8/12 years, height is less than 3rd centile,weight at 50th centile, OFC at the 95th centile. Handlength is at the 3rd centile and foot length is less thanthe 3rd centile. Ear length is normal. The interpupil-lary and outer canthal measurements are greater thanthe 97th centile, but the inner canthal measurement isnear the mean for age (Fig. 2).

Developmental function (Bayley Scales) was between20 and 34 months at chronological age 5 7/12 years.Language skills were at 34 months and motor skills at26 months. On the Peabody Picture Vocabulary Test,

TABLE I. Clinical Manifestations in Affected Males

II-5 II-6 II-9 III-6a IV-1 IV-2

Age at examination—years 62 50 45 5 7 8/12 3 7/12Head circumference—cm (%) 56 (30) 58 (80) 53.2 (<3) 53.5 (98) 54.9 (95) 52.1 (80)Height—cm (%) 160 (<3) 160 (<3) 129 (<3) 99.7 (<3) 114.3 (<3) 84 (<3)Prominent forehead + + + + + +Midface hypoplasia + + + ND 0 0Strabismus ND + + + + 0Inner canthal—cm (%) 3.2 2.4 ND ND 3.0 (60) 2.3 (20)Cataracts/glaucoma + + + 0 0 0Cleft palate 0 0 + 0 + 0Ear length—cm (%) 7.0 (90) 7.8 (>97) 7.4 (>97) ND 6.5 (90) 5.5 (70)Short philtrum + + + ND 0 0Prognathism + 0 0 0 0 0Small hands + + + ND + +Small feet + + + ND + +Inguinal hernia 0 + + + 0 0Testicular volume—cc 20,20 −,7 12,18 ND ND NDStiff digits + + 0 ND 0 0Stiff large joints 0 + + ND 0 0Seizures + + + + + +IQ ND 36 20 <50 66 ND

aInformation from medical records and photographs; ND, observation not available.

Fig. 2. Facial features of IV-1 at 8 4/12 years showing large head, ptosis, hypertelorism, down-slanting palpebral fissures, and up-folded ear lobes; IV-2at age 4 2/12 years showing large head, epicanthus, low-set eyes, and up-folded ear lobes; and II-5 at age 62 years showing tall forehead, postsurgicaltarsorrhaphy of right eye, up-slanting left palpebral fissure, short philtrum, and patulous lower lip.

238 Armfield et al.

he achieved a score of 66 or an age equivalence of 3 5/12years. He now puts two words together, but for themost part still points and occasionally signs. He is ableto write his name. He has experienced global develop-mental delays and requires a special education class-room setting.

The brother (IV-2) of the propositus was macroce-phalic at birth. He experienced neonatal seizures andremained on phenobarbital until age 3 months. He hasexperienced global developmental delays and beganwalking at age 3 years. At age 3 7/12 years, height wasbelow the 3rd centile, weight less than the 3rd centile,and OFC at 80th centile. Hand and foot lengths wereless than 3rd centile. Ear length was normal. The in-terpupillary and outer canthal measurements were atthe 97th centile, but the inner canthal measurementwas below the mean. He had macrocephaly with broadforehead, bilateral epicanthal folds, depressed nasalbridge, mild downslant of the palpebral fissures, low-set posteriorly rotated ears, and small chin (Fig. 2). Anevus flammeus is present over the mid-forehead nasalbridge and nasion.

Growth hormone is abnormally low in both sibs—138ng/ml in IV-1 and <10 ng/ml in IV-2. Ophthalmologicalexamination has shown no evidence for glaucoma todate.

The oldest affected male, II-5, is now 62 years oldand has been institutionalized since age 24 years. Be-tween 6 months and 2 years he had seizures but wasnot treated with anticonvulsants. He had global devel-opmental delay and began walking at age 7 years. Henever attended school. He was described as a nervous,“quick tempered” child. He apparently scratched hislegs frequently in childhood and had multiple bouts ofcellulitis. In adulthood, he developed bilateral open-angle glaucoma and bilateral cataracts. Residual lefthemiparesis followed two strokes. His height is lessthan the 3rd centile, weight at the 10th centile, andOFC at the 30th centile. He has a tall forehead, mildup-slant of the palpebral fissures, large ears, shortphiltrum, prognathism, and a patulous lower lip (Fig.2). There were contractures of the proximal interpha-langeal joints of the third and fourth digits of the lefthand. He is now wheelchair-bound and says only sin-gular words or two-word phrases.

II-6 had a term delivery with birth weight of 4.1 kg.At age 50 years, he was short (160 cm, <3rd centile),had a large head (OFC 58 cm, 80th centile), broad fore-head with central balding, flattened occiput, bilateralglaucoma with prosthetic left eye, up-slanted palpebralfissures, maxillary hypoplasia, large ears with at-tached earlobes, short philtrum, wide mouth, promi-nent tongue, patulous lower lip, small hands and feet,and limited extension of the left elbow. There was a leftinguinal hernia and the left testis could not be pal-pated. The right testis was small (7-cc volume).

II-9, age 45 years at examination, had severe devel-opmental delay, never developing speech or indepen-dent ambulation. He developed seizures during infancythat continued into early adult life. Examinationshowed extreme short stature (129.5 cm height), smallhead circumference (53.2 cm), bilateral blindness sec-ondary to glaucoma, flattened midface, shortened phil-

trum, wide mouth and protruding lower lip, cupping ofthe ears, cleft of the posterior palate, high-riding rightshoulder, small hands and feet, and limited extensionof the elbows.

Information on case III-6, who died at age 19 years instatus epilepticus, was taken from his medical records.At 11 months, a pneumoencephalogram showed mod-erate enlargement of the lateral ventricles, enlargedcystic fourth ventricle, and atrophy of the left cerebralhemisphere. In infancy he had craniofacial asymmetry,bilateral inguinal hernias, and strabismus. He was de-scribed as short with small hands and feet. Headgrowth was along the upper centiles. His developmentwas globally and severely delayed. Developmentalfunction (Bayley Infant Scales) was between 2 and 6months at chronological age 11 months.

Physical examination of obligate carriers I-1, II-2,II-7, III-2, and unaffected brother II-10 showed normalstature and the absence of craniofacial abnormalities.

Linkage Analysis

Twenty-two markers spanning the X chromosomeexcluded all regions except Xq28 (Table II) where a lodscore of 2.11 at zero recombination was observedfor marker p39. Subsequently, another seven markerslocated in Xq27-qter were used to determine the lim-its of the localization. Two other loci, DXS8103 andDXS8061, in Xq28 were found to be tightly linked (Zmax4 2.11, umax 4 0.0) to the XLMR entity in K8100(Table II). Recombination was detected at DXS8011 inproximal Xq28, meaning the region of localizationspanned the most distal 8 Mb of the q arm.

DISCUSSION

An excess of males among individuals with mentalretardation has been recognized worldwide and attrib-uted to mutant genes on the X chromosome [Penrose,1938; Birch et al., 1970; Wing, 1971; Lehrke, 1974;Turner and Turner, 1974; Stevenson et al., 1990]. Thelatter concept has been supported by the clinical andmolecular delineation of a large number of syndromicand nonsyndromic forms of XLMR [Schwartz, 1993;Lubs et al., 1999]. This support notwithstanding, therecognized forms of XLMR fall far short of accountingfor the male excess, which varies from 20–40% in majorsurveys reported during this century. For mutantgenes on the X chromosome to account for an overallexcess of 30% males, such mutations would cause ap-proximately 1 in 7 cases of mental retardation. A fre-quency of this magnitude (∼15% of all cases of mentalretardation) has not been found in major surveys ofmental retardation [Anderson et al., 1996; Hunter etal., 1980; Gustavson et al., 1977; Laxova et al., 1977;Kaveggia et al., 1975; Moser and Wolf, 1971]. Thesesurveys report less than 5% of cases representingXLMR. Only Fryns et al. [1990] have found the fre-quency of XLMR among persons with mental retarda-tion to be as high as 10%.

A number of factors may contribute to the shortfallbetween the estimated prevalence and the identifiableprevalence of X-linked mental retardation. ManyXLMR entities may not have distinctive findings that

XLMR Syndrome Maps to Xq28 239

provide clues to clinical diagnosis. There are very fewentities in which metabolic studies are diagnostic. If asignificant proportion of cases represents new muta-tions, the pedigrees may not suggest X-linkage. Be-

cause females may be affected in many cases, the dis-tinction between XLMR and cultural-familial mentalretardation may be difficult.

The XLMR syndrome described here maps to a re-

TABLE II. Pairwise LOD Scores For X-Chromosome Markers and the XLMR Syndrome in K8100

Marker Locus Location

Recombination (u)

umax Zmax0.001 0.01 0.05 0.1 0.2 0.3

AFM212xes DXS996 Xp22.32 −5.09 −3.10 −1.72 −1.14 −0.59 −0.30 0.50 0.07KAL 58 KAL 58 Xp22.32 −3.59 −1.62 −0.35 0.09 0.33 0.29 0.22 0.34AFM120xa9 DXS987 Xp22.31 −2.09 −1.11 −0.44 −0.19 0.01 0.07 0.50 0.34AFM135xe7 DXS989 Xp22.13 −6.59 −3.62 −1.63 −0.86 −0.27 −0.08 0.34 0.07DXS1110 DXS1110 Xp21.1 −9.59 −5.61 −2.91 −1.82 −0.85 −0.38 0.50 0.04AFM203wf4 DXS993 Xp11.4 −12.29 −7.31 −3.88 −2.47 −0.17 −0.52 0.50 0.02AFM078za1 DXS983 Xq12 −3.59 −1.62 −0.35 0.09 0.33 0.29 0.22 0.34HX60 DXS566 Xq13.3 −2.39 −1.40 −0.72 −0.44 −0.19 −0.08 0.50 0.00AFM116xg1 DXS986 Xq21.1 −3.59 −1.62 −0.35 0.09 0.33 0.29 0.22 0.34AFM249vh5 DXS1002 Xq21.31 −3.90 −1.92 −0.63 −0.17 0.13 0.15 0.50 0.16XL5A DXS424 Xq23 −6.59 −3.62 −1.63 −0.86 −0.24 −0.02 0.50 0.00AFM105xc5 DXS984 Xq27.1 −9.29 −5.31 −2.61 −1.52 −0.57 −0.16 0.44 0.0246 DXS548 Xq27.3 −0.06 0.37 0.93 1.04 0.94 0.66 0.11 1.04DXS1113 DXS1113 Xq28 −0.06 0.37 0.93 1.04 0.94 0.66 0.11 1.04AFMa121ze5 DXS8011 Xq28 −0.06 0.37 0.96 1.04 0.94 0.66 0.11 1.04AFMa065wd9 DXS8103 Xq28 2.11 2.07 1.91 1.70 1.25 0.76 0.00 2.11AFMb311yg1 DXS8061 Xq28 2.10 2.07 1.93 1.74 1.33 0.87 0.00 2.11p39 p39 Xq28 2.10 2.07 1.93 1.74 1.33 0.87 0.00 2.11F8c F8c Xq28 1.80 1.78 1.65 1.49 1.13 0.72 0.00 1.81

Fig. 3. Ideogram showing localization of genes for mucopolysaccharidosis II (IDS), adrenoleukodystrophy (ALD), X-linked hydrocephaly/MASAsyndrome (L1CAM), and MRX41/MRX48 (GDI). Linkage intervals for Kindred 8100 and other entities linked to Xq28 are shown on the right.

240 Armfield et al.

gion known to contain other syndromal and nonsyndro-mal forms of XLMR (Fig. 3). Notable among the syn-dromal forms are X-linked hydrocephaly—MASA [Win-ter et al. 1989], mucopolysaccharidosis II [Le Guern etal. 1990], adrenoleukodystrophy [van Oost et al. 1991],hereditary bullous dystrophy [Wijker et al., 1995], dys-keratosis congenita [Conner et al., 1986], incontinentiapigmenti [Sefiani et al., 1989], ataxia-dementia [Far-low et al., 1987], Waisman-Laxova [Laxova et al., 1985;Gregg et al., 1991], PPM-X [Lindsay et al., 1996],Christian [Dlouhy et al., 1987], Graham [Graham etal., 1990], and Pai syndromes [Pai et al., 1997] . Thepresent entity may be distinguished from these XLMRsyndromes on the basis of clinical findings and meta-bolic studies (adrenoleukodystrophy) and should notbe confused with the nonsyndromal forms of XLMRthat map to Xq28: MRX3 [Gedeon et al., 1991]; MRX6[Kondo et al., 1991]; MRX16 [Moraine et al., 1994];MRX25 [Nordstrom et al., 1992]; MRX28 [Holinski-Feder et al., 1996]; MRX41 [Hamel et al., 1996]; andMRX 48 [des Portes et al., 1997].

The Xq28 region must contain at least three genesinvolved in XLMR based on recent data. Mutations inthe GDI gene have been found in the MRX41 andMRX48 families but not in the MRX3, MRX25, orMRX28 families [D’Adamo et al., 1997]. Because theselatter families are also negative for the FRAXE expan-sion [Gecz et al., 1996], at least one more XLMR genemust reside in Xq28. Futhermore, as syndromic XLMRconditions are probably caused by mutations in genesapart from those responsible for nonsyndromic XLMRand the localized syndromes are quite variable, Xq28likely contains more than four XLMR genes.

ACKNOWLEDGMENTS

We thank members of family K8100 for their coop-eration. This study was funded in part by the NationalInstitutes of Health grant R01 HD26202 to H.A.L. andC.E.S. and a grant from the South Carolina Depart-ment of Special Needs (SCDDSN).

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