Biomedicine International Biomedicine International Biomedicine International Biomedicine International 2013; 4: 45-52.

Address correspondence to Mohammadali M. Shoja, MD, Section of Pediatric Neurosurgery, Children’s of Alabama,

ACC 400, 1600 7th Avenue South, Birmingham, AL 35233, USA. Phone: 205-514-9847. Fax: 205-939-9972. Email:

shoja.m@gmail.com

Submitted November 15, 2012; accepted in revised form November 15, 2012.

For online access, see www.bmijournal.org

CASE REPORT

Lenz-Majewski Syndrome Associated with Hydrocephalus and Multiple

Congenital Malformations

Mohammadali M. Shoja1,2, Martin M. Mortazavi2, Benjamin Ditty2, Christoph J. Griessenauer2,

Marios Loukas3, Alon Harris4, R. Shane Tubbs1

1Section of Pediatric Neurosurgery, Children’s Hospital, Birmingham, AL, USA

2Division of Neurological Surgery, Department of Surgery, University of Alabama at Birmingham, Birming-

ham, AL, USA 3Department of Anatomical Sciences, School of Medicine, St. George’s University, Grenada, West Indies 4Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA

INTRODUCTION

In 1969, Braham described a pediatric patient with several congenital features similar to

Camurati-Engelmann syndrome, symmetric hyperostotic disorder associated with unusual

features of progeria, widened ribs, jaw affection, enamel hypoplasia, webbed hands and

brachysyndactyly.1 This patient was revisited by Macpherson who also suggested it to be

considered “a completely different” condition than Camurati-Engelmann syndrome.2 A

strikingly similar pediatric patient characterized by growth retardation, progeria, choanal

atresia, symphalangism, enamel hypoplasia and craniodiaphysial hyperostosis was later

reported by Lenz and Majewski.3 The constellation of malformations hallmarked by crani-

otubular hyperostosis, ectodermal dysplasia and brachysyndactyly was then further em-

phasized as a distinct entity. So far, this syndrome, which should be appropriately referred

to as Lenz-Majewski syndrome, has only ten reported cases in the English-language litera-

ture. The cases have been sporadically reported from North America1,2,4-6, Europe3,7-9, and

Southeast and Far East Asia.10-12 Herein, the authors describe an additional patient with

ABSTRACT

Lenz-Majewski syndrome is a congenital progressive skeletal disorder hallmarked by craniotubular

hyperostosis, ectodermal dysplasia (cutis laxa and enamel hypoplasia) and hand/foot osseous dys-

genesis or hypoplasia (brachysyndactyly, absent metacarpals, etc). So far, only ten cases of this syn-

drome have been described in literature. We present the eleventh case of Lenz-Majewski syndrome

with craniotubular hyperostosis cutis laxa, brachysyndactyly, hypoplastic fingers and toes and an

absent metatarsal in a Hispanic boy. Notable secondary phenotypic presentations were megalocor-

nea and glaucoma, obstructive sleep apnea, laryngotracheobronchomalacia and severe hydro-

cephalus with intracranial hypertension requiring shunt placement. As far as we are aware, the

latter features have not been previously reported with Lenz-Majewski syndrome. The present re-

port demonstrated the variance associated with the secondary phenotypic burden of this syn-

drome. Biomed. Int. 2013; 4: 45-52. ©2013 Biomedicine International, Inc.

Key words: Congenital, head, malformation, skeletal, skin

BIBIBIBI

SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) 4444::::45454545----52525252

P a g e | | | | 46464646

Lenz-Majewski syndrome associated with multiple unrelated congenital malformations,

which may further extend the phenotypic description of this syndrome. Special emphasis is

made on the course and management of communicating hydrocephalus observed in the

present patient.

CASE REPORT

A 22-month-old Hispanic boy was brought by his mother to our center with swelling over

the back of his head of one-day onset. A history of accidental head trauma due to fall 3-4

days prior to the presentation was obtained from the mother. Initial CT scan revealed a left

frontal small epidural hematoma (<4 mm in width), bilateral posterior subgaleal accumu-

lation, cortical atrophy and ventriculomegaly (Figure 1). On examination, the patient was

alert and reactive with developmental delay. Multiple facial and limb abnormalities were

noted (Figures 2 and 3). The head was large with notable frontal bossing and an open, full

anterior fontanelle. The skin was lax and wrinkled with excessive subcutaneous fat. Subcu-

taneous veins were readily visible, especially over the forehead and scalp. Large palpebral

fissures and slightly bulged eyes were also noted.

Figure 1:

Non-contrast head CT scan. Although left frontal epi-

dural hematoma and bilateral posterior subgaleal ac-

cumulations are acute in appearance, frontotemporal

gyral atrophy, widened subarachnoid space and sulci,

and enlargement of lateral ventricles represent a chron-

ic condition.

The past medical history revealed an otherwise uncomplicated vaginal delivery. Mother

had routine prenatal care and uncertainly stated that the age of biological father was ap-

proximately 25 years at the time of conception. Bilateral cryptorchidism, skeletal abnor-

malities, progeria-like appearance and redundant skin had been noted in early infancy.

The early-infancy skeletal X-ray survey had shown generalized osteopenia, diffuse diaph-

yseal sclerosis, metaphyseal lucency, frontal bone sclerosis, widened clavicles, ribs and is-

chia, hypoplastic metatarsals and metacarpals and bilateral absence of one metatarsal, con-

sistent with the clinicoradiological diagnosis of Lenz-Majewski syndrome. Head CT scans

had demonstrated slight prominence of extra-axial spaces and enlarged basilar cisterns at

2-months of age, and mildly dilated lateral and third ventricles and prominent sulci and

cisterns at 4-months of age. A small patent ductus arteriosus, patent foramen ovale, mildly

dilated right atrium and ventricle were noted on initial echocardiography but later re-

BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) 4444: : : : 45454545----52525252 / LENZ/ LENZ/ LENZ/ LENZ----MAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROME

P a g e | | | | 47474747

solved. The patient underwent surgery for choanal atresia and nasolacrimal duct obstruc-

tion as well as small bowel resection and ileostomy creation due to necrotizing enterocol-

itis-related bowel adhesions and stricture formation in early infancy. This was followed by

closure of ileostomy and laparotomy with Roux-en-Y feeding jejunostomy for gastric iner-

tia and feeding intolerance at 6 and 11 months of age, respectively. At 7-months of age, an

ocular examination under anesthesia revealed bilateral congenital glaucoma and megalo-

cornea. A skeletal X-ray survey at 14-months of age had revealed diffuse skeletal dysplasia,

osteosclerosis and osteopenic appearance; the characteristic findings were craniofacial dis-

proportion with bulbous calvarial contour, frontal prominence and midface dysplasia,

widened ribs and clavicles, osteosclerosis and undertubulation of the long bones in the up-

per and lower extremities and hypoplasia of metacarpals, hand and foot phalanges and bi-

lateral absence of one metatarsal. A repeat head CT scan at 14-months also had demon-

strated increased dilation of the lateral and third ventricles compared to a scan performed

at 4 months. At 17-months, the patient underwent bilateral myringotomy tube placement

for chronic otitis media and mucoid effusions, which was complicated by postoperative

pneumonia, respiratory failure and obstructive sleep apnea. A bronchoscopy at that time

revealed pharyngeal hypotonia (perhaps due to decreased muscular tone and/or connec-

tive tissue disorder), laryngomalacia and tracheobronchomalacia. He underwent a nasal

septoplasty for a deviated septum and severe nasal obstruction at 19 months, and contin-

ued to receive nighttime bilevel positive airway pressure (BiPAP) for obstructive sleep ap-

nea.

Figure 2: Patient’s facial features upon presentation with hydrocephalus (2a) and at 50 months of age (2b). 2a,

Progeroid appearance, frontal bossing with visible subcutaneous veins, hypertelorism, depressed nasal bridge and broad

nasal tip, flared nares, malformed ears, and thickened upper lip are remarkable. 2b, Note the box-shaped head.

With a diagnosis of hypertensive hydrocephalus, the patient then underwent a right ven-

triculoperitoneal shunt insertion at 22 month of age. Notable during subcutaneous tunnel-

ing for shunt placement was significant venous engorgement and abnormally dense con-

nective tissues. Significant collapse of his ventricles was noted on the repeat head CT scan

9 days later. Repeat CT scans also revealed narrowing of the foramen magnum, which

could potentially explain the occurrence of hydrocephalus in this patient. Unfortunately, 8

months later, the patient presented with a wound dehiscence, shunt infection and subse-

SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) 4444::::45454545----52525252

P a g e | | | | 48484848

quent formation of subdural empyema. The shunt was removed; an external ventricular

drain was placed. The postoperative course was complicated by formation of a subdural

empyema, which was managed by left frontal small craniotomy and irrigation. Eventually,

an occipital ventriculoperitoneal shunt was inserted. A follow-up CT scan three months

later showed interval decompression of the lateral ventricles. Five months later the patient

was readmitted for symptoms of shunt failure consisting of bradycardia and apneic spells

and underwent emergent external ventricular drain placement. The hospital course was

complicated by intraparenchymal and intraventricular hemorrhages associated with cathe-

ter placement, failure after shunt re-insertion and development of ventriculitis requiring

prolonged external ventricular drainage and antibiotic therapy. Technical challenges relat-

ed to the underlying syndromic features such as thin skin and dense soft tissue were en-

countered with these surgeries. Eventually, a shunt was replaced and the patient was dis-

charged home. Within a few days, he had to be readmitted for recurrent shunt failure and

respiratory failure requiring ventilator support and tracheostomy placement. At this point

the patient had a shunt reinserted but was not discharged from the hospital due to persis-

tent respiratory issues and sepsis. A repeat hand and foot X-ray was performed at 48

months of age, which in comparison to an earlier X-rays (Figure 4) showed the severely

progressive nature of osteosclerosis (Figure 5).

Figure 3: Photographs of right (3a) and left hands (3b) and right (3c) and left feet (3d) at 50-51 months of age (note that

earlier images were of low-quality and are not shown here). Wrinkled skin, brachydactyly, cutaneous syndactyly,

hyperconvex nails, and short foot with dorsiflexed toes are remarkable.

BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) 4444: : : : 45454545----52525252 / LENZ/ LENZ/ LENZ/ LENZ----MAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROME

P a g e | | | | 49494949

Figure 4: Skeletal X-rays (at 22 months of age) showing osteosclerosis of skull base and orbital rim and midface

hypoplasia (a), osteosclerosis of long bones, metaphyseal lucency and bilateral agenesis of a metatarsal and

undermodeling/hypoplasia of metatarsals and toe phalanges (b, c and d), and widened ribs (e).

Figure 5: Hand and foot X-ray at 48 months of age. Severely progressive osteosclerosis is evident in comparison to Figure

4. Brachydactyly, symphalangism, phalangeal hypoplasia, underdeveloped carpal bones (A), epiphyseal/metaphyseal

lucency, sclerotic and thickened cortical bone (B), and absent metatarsal and underdevelopment of tarsal bones (C) are

remarkable.

SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) 4444::::45454545----52525252

P a g e | | | | 50505050

DISCUSSION

Lenz-Majewski syndrome is a distinct form of craniotubular bone dysplasia characterized

by progressive craniotubular hyperostosis and osteosclerosis (thickened calvaria, ribs, and

diaphyseal bones), ectodermal dysplasia (e.g., enamel hypoplasia, cutis laxa), proximal

symphalangism/syndactyly and disproportionate brachydactyly. Proximal symphalangism

is often associated with interdigital webbing or cutaneous syndactyly. Characteristic skele-

tal finding of Lenz-Majewski syndrome were present in our patient, although abnormali-

ties of foot (e.g., absent metatarsal) were more dominant than hands (Figures 4 and 5). A

Lenz-Majewski syndrome-like syndrome has also been reported in a Japanese boy with

limited tubular osteosclerosis, and rather-proportionate shortening of the digits without

symphalangism.12 The 2006 revised edition of Nosology and Classification of Genetic Skel-

etal Disorders included this syndrome (together with such syndromes as Camurati-

Engelmann, Tricho-dento-osseous dysplasia, Pachydermoperiostosis, etc.) under the cate-

gory of increased bone density with metaphyseal and/or diaphyseal involvement.13 The ge-

netic basis of Lenz-Majewski syndrome is still unknown and chromosomal studies have

failed to show a gross abnormality; however, several patients reported previously had been

associated with older paternal age. Although such an association cannot be fully justified

based on the limited reports, one may refer to other congenital skeletal malformations as-

sociated with advanced paternal age such as achondroplasia and acrocephalosyndactyly,

potentially linked to increased likelihood of mutation in the aged spermatozoon.14 Notably,

the family history was positive for a sibling with Down syndrome in the patient described

by Braham1 and Macpherson.2

The prognosis of Lenz-Majewski syndrome is often poor due to multiple and progressive

congenital deformations, failure to thrive and developmental delay. The patients may die

early in the neonatal period5, or as Majewski noted, may survive until adulthood with no

serious illness.8 Heterogeneous presentations and non-classic findings in Lenz-Majewski

syndrome have been reported by previous authors. Cerebral agenesis and micrognathia1,

cryptorchidism2,6,7, lumbar spina bifida occulta and hemivertebra7, ambigous genitalia5,

hypospadias5,6, Chordee6, exophthalmia12, communicating hydrocephalus, cleft palate, per-

sistent peripheral facial palsy11, choanal stenosis, hip dysplasia and strabismus3,8, humero-

radial synostosis7, nasolacrimal duct obstruction4,9, dysgenesis of corpus callosum and mild

white matter atrophy9, prognathism10, and conductive hearing loss7 have also been report-

ed. In a postmortem examination by Kaye and colleagues no gross abnormality was noted

in the internal organs including brain.5 Lenz-Majewski syndrome is in differential diagno-

sis of a group of genetic skeletal disorders which are associated with hyperostosis and di-

aphyseal dysplasia.13 A classic example is Camurati-Engelmann’s syndrome, a progressive

tubular bone dysplasia. In a previous report, enamel hypoplasia, abnormal modeling of

long bones and cutaneous abnormalities such as cutis laxa have been described as parts of

the so-called SCARF syndrome.16 However, involvement of hands and feet (e.g., symphal-

angism, brachysyndactyly and absence or hypoplasia of the small bones) in association

with craniodiaphyseal hyperostosis (dysplasia) is characteristic for Lenz-Majewski syn-

drome.

Table 1 compares the clinical feature of the present patient and the one originally de-

scribed by Lenz and Majewski.3 The present patient had characteristic clinicoradiological

features of Lenz-Majewski syndrome including cutis laxa, craniotubular hyperostosis and

brachydactyly. He additionally had an absent metatarsal. Other notable malformations

BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) BIOMED INT (20131) 4444: : : : 45454545----52525252 / LENZ/ LENZ/ LENZ/ LENZ----MAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROMEMAJEWSKI SYNDROME

P a g e | | | | 51515151

were communicating hydrocephalus (secondary to skull base hyperostosis and narrowing

of the foramen magnum, impairment of cerebral venous outflow or decreased cerebrospi-

nal fluid absorption), glaucoma and megalocornea (perhaps due to excess laxity of corneal

stroma), cryptorchidism (due to gubernacular connective tissue changes) and laryngotra-

cheobronchomalacia. A mild dilation of lateral ventricles was also reported by Gorlin and

Whitley4 in a patient with no evidence of intracranial hypertension and no need for inter-

vention. Macrocephaly and mild dilation of lateral ventricles were described in a Japanese

boy with atypical Lenz-Majewski syndrome characterized by mild undertubulation of met-

acarpals and proximal phalanges and dominantly metaphyseal involvement of tubular

bones; no intervention was reported for mild hydrocephalus.12 In a patient with communi-

cating hydrocephalus, Wattanasirichaigoon and colleagues reported a good response to

carbonic anhydrase inhibitor, and attributed the cause of hydrocephalus to an impaired

intracranial venous drainage and cerebrospinal fluid absorption.11

Table 1: Comparison of clinical features of the present patient with the original report of Lenz and Majewski (1974)

Clinical Features Present patient Lenz and Majewski’s patient

Gender Male Female

Craniodiapyseal hyperostosis + +

Symphalangism + +

Brachysyndactyly + +

Hypertelorism + +

Enamel hypoplasia + +

Dermopathy + +

Hydrocephaly + -

Glaucoma + -

Laryngotracheobronchomalacia + -

Obstructive sleep apnea + -

Ultimately, the present report added a new case of Lenz-Majewski syndrome to the ex-

tant literature. Aside from typical features of the syndrome, novel associations with this

rare syndrome included hydrocephalus with intracranial hypertension requiring shunt

placement, glaucoma/megalocornea as well as laryngotracheobronchomalacia leading to

obstructive sleep apnea. As far as we are aware, the latter features have not been previously

reported with Lenz-Majewski syndrome. In agreement with previous reports, our report

demonstrated the variance associated with the secondary phenotypic burden of this syn-

drome.

REFERENCES

1. Braham RL. Multiple congenital abnormalities with diaphyseal dysplasia (Camurati-Engelmann syn-

drome). Oral Surgery 1969; 27: 20-6.

2. Macpherson RI. Craniodiaphyseal dysplasia, a disease or group of diseases? J Canad Assoc Radiol 1974;

25: 22-33.

3. Lenz WD, Majewski F. A generalized disorders of the connective tissues with progeria, choanal atresia,

symphalangism, hypoplasia of dentine and craniodiaphyseal hypostosis. Birth Defects Orig Artic Ser

1974; 10: 133-6.

4. Gorlin RJ, Whitley CB. Lenz-Majewski syndrome. Radiology 1983; 149: 129-31.

5. Kaye CI, Fisher DE, Esterly NB. Cutis laxa, skeletal anomalies, and ambiguous genitalia. Am J Dis Child

1974; 127: 115-7.

6. Robinow M, Johanson AJ, Smith TH. The Lenz-Majewski hyperostotic dwarfism. A syndrome of multi-

ple congenital anomalies, mental retardation, and progressive skeletal sclerosis. J Pediatr 1977; 91: 417-

21.

7. Chrzanowska KH, Fryns JP, Krajewska-Walasek M, et al. Skeletal dysplasia syndrome with progeroid

appearance, characteristic facial and limb anomalies, multiple synostoses, and distinct skeletal changes: a

variant example of the Lenz-Majewski syndrome. Am J Med Genet 1989; 32: 470-4.

SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) SHOJA ET AL. / BIOMED INT (2013) 4444::::45454545----52525252

P a g e | | | | 52525252

8. Majewski F. Lenz-Majewski hyperostotic dwarfism: reexamination of the original patient. Am J Med

Genet 2000; 93: 335-8.

9. Saraiva JM. Dysgenesis of corpus callosum in Lenz-Majewski hyperostotic dwarfism. Am J Med Genet

2000; 91: 198-200.

10. Dateki S, Kondoh T, Nishimura G, et al. A Japanese patient with a mild Lenz-Majewski syndrome. J

Hum Genet 2007; 52: 686-9.

11. Wattanasirichaigoon D, Visudtibhan A, Jaovisidha S, et al. Expanding the phenotypic spectrum of Lenz-

Majewski syndrome: facial palsy, cleft palate and hydrocephalus. Clin Dysmorphol 2004; 13: 137-42.

12. Nishimura G, Harigaya A, Kuwashima M, et al. Craniotubular dysplasia with severe postnatal growth

retardation, mental retardation, ectodermal dysplasia, and loose skin: Lenz-Majewski-like syndrome.

Am J Med Genet 1997; 71: 87-92.

13. Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J

Med Genet A 2007; 143: 1-18.

14. Risch N, Reich EW, Wishnick MM, et al. Spontaneous mutation and parental age in humans. Am J Hum

Genet 1987; 41: 218-48.

15. Koppe R, Kaplan P, Hunter A, MacMurray B. Ambiguous genitalia associated with skeletal abnormali-

ties, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome).

Am J Med Genet 1989; 34: 305-12.