Brief Clinical Report

Spinal Muscular Atrophy Variant WithCongenital Fractures

Thaddeus E. Kelly,1* Kathy Amoroso,2 Merry Ferre,2 John Blanco,1 Patricia Allinson,1 andThomas W. Prior3

1University of Virginia School of Medicine, Charlottesville, Virginia2Community Hospital of the Roanoke Valley, Roanoke, Virginia3Ohio State University, Columbus, Ohio

A single report of brothers born to first-cousin parents with a form of acute spinalmuscular atrophy (SMA) and congenitalfractures suggested that this combinationrepresented a distinct form of autosomal re-cessive SMA. We describe a boy with hypo-tonia and congenital fractures whose suralnerve and muscle biopsies were consistentwith a form of spinal muscular atrophy. Mo-lecular studies identified no abnormality ofthe SMNT gene on chromosome 5. This caseserves to validate the suggestion of a dis-tinct and rare form of spinal muscular atro-phy while not excluding possible X-linkedinheritance. Am. J. Med. Genet. 87:65–68,1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: spinal muscular atrophy;congenital fractures; reces-sive inheritance

INTRODUCTION

Borochowitz et al. [1991] described 2 brothers of afirst-cousin mating with an acute spinal muscular at-rophy (SMA) and congenital fractures. The pedigreewas considered strongly suggestive of autosomal reces-sive inheritance although X-linked inheritance couldnot be excluded. We describe an additional case in aboy.

CLINICAL REPORT

This boy was born at term to an 18-year-old gravida2 para 1 mother by cesarean section for breech presen-

tation. The Apgar scores were 1, 5, and 6 at 1, 5, and 10min, respectively. He was noted to be small for gesta-tional age (birth weight 2,420 g) and severely hypotonicwith multiple joint contractures and a valgus deformityof the right foot. Intubation and ventilatory supportwere required. He was extubated on the 2nd day of lifeand did well in room air but had a weak suck and fedpoorly. Radiographs showed bilateral femoral fractureswith generalized osteopenia. On Day 14 he was trans-ferred to the University Hospital for further evalua-tion. On arrival, respirations were 40 breaths per min,blood pressure 103/69 mm Hg, weight 2475 g, length46.2 cm (both below 5th centile), head circumference 35cm (50th centile), and oxygen saturation on room airwas 99%. His physical findings were normal apart fromthe musculo–skeletal system. The face was myopathicand there was decreased muscle mass of the limbs.

There were contractures at elbows, knees, and hipswith bilateral valgus deformities of the feet and ulnardeviation of the hands. There was swelling and pal-pable callus in both thighs and in the right upper arm.Results of serum chemistry studies were normal in-cluding calcium, magnesium, phosphate, alkalinephosphatase, and lactate dehydrogenase.

Radiographs disclosed the previously noted femoralfractures and a healing fracture of the right humerusand periosteal reaction along the shaft of the left hu-merus consistent with a healed fracture. Generalizedosteopenia was noted (Fig. 1–4). Nerve conductionstudies showed low amplitude median and ulnar nerveresponses whereas ulnar sensory responses were unob-tainable. Concentric needle examination of selectedmuscles demonstrated profuse fibrillation potentialsand sparse, rapidly firing, markedly enlarged motorunit potentials. The findings were felt to demonstrate asevere motor neuropathic disorder. A sural nerve bi-opsy from the left leg showed a decrease in intensity ofthe large myelinated fibers when compared to an age-matched control. Electron microscopy showed a de-crease in axonal diameter and myelin sheath thick-ness. Intraaxoplasmic accumulations of membranousdebris and vacuolated material were suggestive of axo-

*Correspondence to: Thaddeus E. Kelly, M.D., Ph.D., Box 386,University Hospital, Charlottesville, Virginia, 22908.Email: TEK8S@Virginia.edu

Received 30 March 1999; Accepted 24 June 1999

American Journal of Medical Genetics 87:65–68 (1999)

© 1999 Wiley-Liss, Inc.

nal degeneration. The muscle biopsy showed variabil-ity in size of type 1 and type 2 fibers with the largestfibers approximately three to four times the smallestfibers. Histochemical stains for phosphorylase, glyco-gen, and lipid as well as mitochondrial, branching, andadenosine deaminase enzymes were normal.

At the time of the biopsies, a feeding gastrostomywas placed and the infant tolerated gastrostomy feed-ing well. He was discharged to the care of his parents.At 2 months he was admitted to the local hospital witha respiratory infection and required mechanical venti-lation for 4 days. A Nissen fundoplication was per-formed based on a clinical diagnosis of reflux with as-piration. Following discharge he received physical, oc-cupational, and respiratory therapy at home. At 3months he was seen for follow up. His weight was 3,100g, length 53 cm, and OFC 38 cm (all below the 5thcentile for age). Severe hypotonia persisted with poorhead control. There had been no new fractures and hislimbs showed mild angulation deformities, but his jointcontractures were improved. No deep tendon reflexescould be elicited and muscle bulk was minimal.

At 31⁄2 months of age he developed a respiratory in-fection resulting in tachypnea and cyanosis. Whenbrought to the local emergency room, he was dead onarrival. The family did not authorize an autopsy.

The older sib was a normal boy, and later, the family

had a third child, a normal girl. The parents were notconsanguineous.

Molecular Studies

In the neonatal period, a blood sample was submit-ted for DNA studies that showed the absence of homo-zygosity for a deletion of exons 7 and/or 8 of the SMNT

gene (Genzyme).At a later date, DNA from a residual portion of the

muscle biopsy was analyzed by densitometric analysisand failed to show heterozygosity for a SMNT deletion(McAndrew et al., 1997). Because SMNT exon 7 is ho-mozygously deleted in 95% of 5q SMA cases, then ac-cording to Hardy-Weinburg equilibrium, virtually allthe remaining 5q SMA individuals should have a het-erozygous deletion. Finally, DNA from peripheral bloodof the parents was analyzed by SSCP for the entirecoding region of the telomeric form of SMN and nopoint mutations were detected.

DISCUSSION

The EMG and muscle biopsy findings in this case areconsistent with 5q SMA, albeit with evidence for a sen-sory component. However, the presence of a myopathicface, congenital contractures, and evidence of sensorynerve changes remain part of the exclusion criteria of

Fig. 1. Right humeral fracture. Fig. 2. Periosteal reaction along the shaft of the left humerus.

66 Kelly et al.

the International SMA Consortium. The absence of anulnar nerve response on nerve conduction testing andthe light microscopy and EM findings of the sural nervebiopsy are suggestive of a peripheral neuropathy. Priorto the mapping of SMA to 5q, this case would not havebeen considered to represent infantile SMA, or Werd-nig-Hoffmann syndrome. With the advent of analysis ofthe SMN gene, it has become apparent that SMA I

encompasses a broader phenotype than previouslythought. Omran et al. [1998] reported on sibs with anaxonal neuropathy and predominance of type II myofi-brils who demonstrated homozygous deletions ofSMNT; however, these cases did not have congenitalfractures.

This case suggests that SMA with congenital frac-tures as described by Borochowitz et al. [1991] is adistinct entity. However, the possibility remains thatthis may represent variation on several established en-tities.

Occasionally, infants with the classic form of Werd-nig-Hoffman SMA present with contractures in thenewborn period, apparently as a result of in uteroweakness. However, fractures are not present at birthand death usually occurs later in infancy. Although thepossibility remains that a mutation at the SMNT locuscould be present in this case, this seems unlikely. Intheir identification of the SMN gene, Lefebvre et al.[1995] reported that 226 of 229 SMA patients had adeletion or interruption of the SMNT gene and pointmutations or short deletion were detected in the re-maining 3. The parents of the case reported hereinwere not consanguineous, thus, the probability of anundetected SMNT point mutation seems remote.

Hypotonia and arthrogryposis are seen in a form ofcongenital myopathy inherited as an autosomal reces-sive disorder [Pearson and Fowler, 1963]. This disorderdiffers from our case in that it is a myopathy, and nota neuropathy, and congenital fractures have not beenreported.

Bruck syndrome is an autosomal recessively inher-ited disorder with neonatal contractures and congeni-tal fractures [Viljoen et al., 1989]. These infants do notdemonstrate severe weakness, fractures continue afterbirth, and life expectancy is well beyond that observedin this disorder.

Borochowitz et al. [1991] suggested autosomal inher-itance, as the parents of their cases were first cousins.However, both affected infants were male as was thecase reported here. X-linked disorders with hypotoniaand arthrogryposis include a form of infantile spinalmuscular atrophy reported by Greenberg et al. [1988]and a form of lethal spinal muscular atrophy reportedby Kobayashi et al. [1995]. In neither condition werecongenital fractures reported.

Arthrogryposis multiplex congenita is a descriptivediagnosis of heterogeneous cause. A common compo-nent is decreased fetal movement. Severe osteopeniaand fractures are sometimes seen in premature in-fants. In the case described here, the joint contracturesapparently reflected extreme fetal hypotonia with sec-ondary osteopenia resulting in long bone fractures. Al-though the case reported here serves to further delin-eate the disorder described by Borochowitz et al.[1991], additional cases will be required to determinewhether the mode of inheritance is autosomal or X-linked. Study of additional cases will also be requiredto determine whether this disorder represents muta-tion at the locus of one of the disorders described ear-lier, or at a currently undefined locus.Fig. 4. Varus deformities of the feet and striking osteopenia.

Fig. 3. Old fracture of the left femur and periosteal reaction along theshaft of the right femur.

SMA and Congenital Fractures 67

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