American Journal of Medical Genetics 47:534-539 (1993)

DOOR Syndrome (Deafness, Onycho- Osteodystrophy, and Mental Retardation): A New Patient and Delineation of Neurologic Variability Among Recessive Cases

Henry J. Lin, Emil D. Kakkis, Donna J. Eteson, and Ralph S . Lachman Division of Medical Genetics, Departments of Pediatrics (H.J.L., E.D.K.) and Radiology (R.S.L.), Harbor-UCLA Medical Center, Torrance, California, and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California (D . J.E .)

We report the seventeenth case of the reces- sive form of the DOOR syndrome. The parents were Guatemalan and not known to be con- sanguineous. The patient had developmental delay, severe sensorineural deafness, and ab- normal nails and phalanges in the hands and feet. Urinary 2-oxoglutarate excretion was normal. The patient was among a subset of DOOR syndrome patients without seizures in infancy. This observation may be useful in discussing the prognosis for newly identified cases. 0 1993 Wiley-Liss, Inc.

KEY WORDS: DOOR syndrome, onychodys- trophy

INTRODUCTION The DOOR syndrome [Cantwell, 19751 is charac-

terized by mental retardation, sensorineural deafness, and dysplastic nails and distal phalanges of the hands and feet. Some 20 cases have been reported since 1961 from Israel, the United States, France, Puerto Rico, the Philippines, Venezuela, Ireland, Italy, Pakistan, and other parts of northern Europe and Latin America. Four patients in 2 families, including the Filipino family and a US. family, had a dominantly-inherited form of the DOOR syndrome, whereas 16 patients in 12 families had an autosomal recessive form.

We report on a Guatemalan girl, representing the fifth Hispanic family with recessive DOOR syndrome [Qazi and Smithwick, 1970; Cantwell, 1975; Sanchez et al., 1981; Qazi and Nangia, 19841. The patient was de- velopmentally delayed, deaf, and had the classic digital

Received for publication February 1,1993; revision received May 3, 1993.

Address reprint requests to H. J. Lin, M.D., Division of Medical Genetics, E4, Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502.

0 1993 Wiley-Liss, Inc.

abnormalities. Although all patients with recessive DOOR syndrome have a major disability due to mental retardation, our patient and 3 other families support dividing the recessive form into different groups, accord- ing to clinical severity. A distinguishing manifestation is the occurrence d seizures in infancy. The classifica- tion may be useful in predicting the course of the condi- tion and supports the interpretation of multiple muta- tions conferring different phenotypes.

CLINICAL REPORT The patient, a 3,912 g female at birth, was the product

of a term pregnancy and uncomplicated delivery to a healthy, 18-year-old, gravida 1 mother. The father (25- years-old) and grandparents were normal. The families of both parents were from Guatemala City but were nonconsanguineous. Absence of nails on the toes and on the 1st and 5th fingers was noted at birth. She grew normally during childhood, with weight and length at approximately the 25 th centile. Head circumference was at the 50th centile. There were no feeding problems or serious illnesses. Chromosomes were normal.

When seen at 4% months, she was able to smile and roll. She sat alone at 11 months and walked with support at 16 months. A Gesell developmental evaluation at 17 months (74 weeks) indicated an overall developmental quotient of 68, with severe hearing loss and no speech development. (The developmental quotient was 73 when language delay was disregarded.) Audiologic testing showed equivocal response to 88 decibels and no re- sponse to brainstem evoked potentials. At 20 months, she was enrolled in a school for the hearing impaired.

The patient watj evaluated at 8 years for staring spells and occasional unusual twisting and turning move- ments. Cranial nerves, motor strength, tone, and re- flexes were normal. She had poor rapid alternating hand movements. An electroencephalogram (EEG) showed definite central spike discharges on multiple occasions in association with spindle activity. There was no evi- dence of focal slowing, hemispheral asymmetry, or epi- leptiform discharges. There had never been a docu-

DOOR Syndrome 535

mented convulsion. Ethosuximide was given for approximately one year with no change in symptoms.

At 11-12 years, there were changes in behavior, char- acterized by unpredictable behavior in public, excess noise, inappropriate removal of clothing, and wander- ing. There was one admission to a pediatric psychiatry ward following an outburst in school. Menses began at 12 years. Height was at the 25th centile with weight a t the 75th centile. She had severe bilateral sensorineural hearing loss and no acoustic reflexes. A CT scan of the head showed a normal appearing ventricular system, no intracranial mass effect, and no anomalies. There was no epileptiform activity on EEG. Receptive language ability assessed by use of the Carolina Picture Vocabul- ary Test indicated receptive sign language skills a t the 59/iz year level.

She was attending a speech and language school at 14 years, was able to read a few words, and communicate in sign language with her mother. An ophthalmologic ex- amination showed the visual acuity to be 20130 in both eyes. Nystagmus was absent. The conjunctivae, lenses, and optic nerves were normal. There were no nails on the thumbs, fifth fingers, or toes (Fig. 1). There were single palmar creases on both hands and very promi- nent McIntosh pads on the thumbs (Fig. 2). Digits 1-4 of both hands had arch patterns. The 5th fingers had dou- ble whorls, clearer on the left (Fig. 3). The total ridge count was less than 5, the absolute ridge count was less than 10, and the ab ridge count was 83 (normal). Both hands had an atd angle of 52" and an interdigital tri- radius near the c and d triradii. All of the toes had arch patterns.

Urine organic acids, including 2-oxoglutarate (19 mmollmol of creatinine), were normal.

The patient's mother had normal radiographs of the hands and feet a t age 21. Audiometry was also normal. The father was unavailable for testing but by history

Fig. 1. Absence of nails on the thumbs and 5th fingers, dystrophic nails on the 2nd, 3rd, and 4th fingers, excess soft tissue at the tips of the thumbs, and absence ofthe distal phalanges of the 5th fingers (age 14).

Fig. 2. Excess soft tissue at the tips of the thumbs, absence of distal phalanges of the 5th fingers, and single palmar creases (age 14).

had no abnormalities of the hands or feet and no hearing impairment.

SKELETAL FINDINGS Three sets of radiographs of the hands taken between

the newborn period and 27 months of age (Figs. 4 and 5) showed either hypoplasia or absence of ossification of distal phalangeal tufts. Loss of tuft ossification of the 5th digit was also associated with absence of soft tissues. The distal phalanx of the thumb was somewhat hypo- plastic with excess soft tissue in the region. Films at age 13 months showed the absence of the terminal phalanx of the 5th digit of both hands as well as hypoplasia of some of the tufts and some of the middle phalanges. Films at 12 years (Fig. 6) showed absence of the distal phalanges of the 5th fingers. There was hypoplasia of the distal phalanges of the 2nd, 3rd, and 4th digits of both hands. Although the distal phalanx of the left thumb was normal, the right distal phalanx was some- what hypoplastic.

Radiographs of the feet (not shown) taken neonatally showed evidence of bilateral clubfoot deformity and dis- tal phalangeal hypoplasia in the feet. Between the ages of 13 and 27 months, there was hypoplasia of the distal phalanges of both great toes, absence of ossification of the distal phalanges of the 2nd, 3rd, 4th, and 5th toes, and apparent hypoplasia of the middle phalanx of both 5th toes. At 12 years, the distal phalanges of the 2nd, 3rd, 4th, and 5th toes were absent, with hypoplasia of the middle phalanx of these toes. The distal phalanx of the great toes were short, but wide, and hypoplastic with excess soft tissue in the region.

The remaining skeleton that was examined in detail was entirely normal. These radiographic findings are similar to those described by Thomas and Nevin t19821 and mentioned by other authors.

536 Linetal.

Fig. 3. Double whorl pattern on the left 5th finger (age 15).

Fig. 4. Radiograph of the left hand [birth (A) and 13 months (B)] showing hypoplasia of the 2nd, 3rd, and 4th distal phalanges; absence of the 5th distal phalanx; hypoplasia of the distal phalanx of the thumb with soft tissue enlargement.

DOOR Syndrome 537

Fig. 5. Radiograph of the right hand (27 months). Findings similar to those in Figure 4A and B, with normal development of epiphyseal centers for age; increasing size of the hypoplastic 3rd and 4th distal phalanges and ossification of round, enlarged epiphyses of these two bones; a very hypoplastic distal phalanx of the 2nd finger; and continu- ing absence of any distal phalangeal ossification of the 5th digit.

RADIOGRAPHIC PATTERN PROFILE ANALYSIS

Pattern profiles (Fig. 7) were derived from hand radio- graphs obtained at age 12, according to the method of Poznanski [19741. The profiles ofthe right and left hands were similar, although the bones of the right hand were smaller than those of the left. The largest dip in the profiles represented absence of the distal phalanges of the fifth fingers.

DISCUSSION Within the recessive form of the DOOR syndrome,

important variability occurs in its neurological mani- festations. Our patient and 4 others exemplified a some- what milder neurological phenotype in which seizures in the 1st few years of life did not occur. The 5 nonepilep- tic patients had been followed for 15, 11, 10, and 3% years [present case; Nevin et al., 1982; Feinmesser and Zelig, 1961; Walbaum et al., 19701 and into school age [Feinmesser and Zelig, 19611. The nonepileptic patient of Nevin et al. [1982] had a left hemiparesis at age 2, but

In contrast, 11 patients had convulsions beginning at approximately one year [Qazi and Smithwick, 1970; Cantwell, 1975; Sanchez et al., 1981; Nevin et al., 1982; Qazi and Nangia, 1984; Patton et al., 19871. Seizures began as early as 2 days to 3 months in 6 patients and were difficult to control in 8 patients. The severely af- fected patient reported by Hess and Pecotte [1984] had her first seizure at 14 months [J.K. Pecotte, personal communicationl. None of the seizures was associated with developmental defects of the brain detectable by CT scanning.

There were 4 families in which 2 affected sibs were described. The phenotypes appeared to be concordant in at least 3 families [Feinmesser and Zelig, 1961; Sanchez et al., 1981; Qazi and Nangia, 19841. The 4th family had a nonepileptic patient and an affected 13-year-old sister whose seizures were controlled with anticonvulsants [Walbaum et al., 19701. However, the age of onset of her seizures was not recorded.

Results of formal developmental or intelligence test- ing were reported in only 4 patients [Walbaum et al., 1970; Cantwell, 1975; Nevin et al., 1982; present case]. Therefore it was not possible to correlate developmental or intelligence quotients with other parts of the DOOR syndrome phenotype. All patients who were formally tested had developmental or intelligence quotients be- tween 32 and 45.

There were more ocular abnormali.cies among the pa- tients with early seizures [Nevin et al., 1982; Hess and Pecotte, 1984; Patton et al., 19871. These included nystagmus, blindness, optic atrophy or hypoplasia, slow pupillary responses, high myopia, and a cataract. Strabismus was reported in one of the less severely af- fected patients [Feinmesser and Zelig, 19611. Our pa- tients had no retinal or optic nerve abnormalities.

Four recently described patients had high levels of urinary 2-oxoglutarate, and at least 3 of these patients had severe seizures [Patton et al., 19871. The finding is of interest, because it provides a potential clue to the un- derlying defect. However, urinary 2-oxoglutarate excre- tion was not elevated in our patient. One possibility is that the oxoglutaric aciduria is related to the more se- vere phenotype. Analysis of urine organic acids of other patients is needed to determine the frequency and dis- tribution of this biochemical abnormality in the DOOR syndrome.

The radiographic manifestations of the syndrome ap- pear to be fairly uniform, with some exceptions. The occurrence of triphalangeal thumbs, for example, is variable and unrelated to clinical severity. In one family with 2 affected sibs, triphalangeal thumbs were present in one child but absent in the other [Qazi and Nangia, 19841. There may also be differences in interpretation of the skeletal findings from case to case. For example, the radiographic manifestations of the feet of our patient were consistent with either loss of a distal phalanx in association with a middle phalanx that assumes the architecture of the distal, or alternatively, loss of the middle phalanx with normal tuft development.

We used radiographic pattern profiles to characterize the relative bone lengths in the hands. The major waves

none of the others had associated motor deficits. of the pattern profile of our patient reflected absence of

538 Lin et al.

Fig. 6. Radiograph of the hands [left (A) and right (B); age 121. Findings similar to those in Figures 4 and 5, with near closure of many distal epiphyseal plates; bottle-shaped 3rd and 4th distal phalanges; and hypoplastic 2nd distal phalanges. For reference, the length of the left 2nd metacarpal is 51 mm.

the distal phalanges of the 5th fingers, shortness of the 2nd distal phalanges, and shortness of the 5th metacar- pals. Other patients are needed to determine if the pat- tern profile correlates with the clinical phenotype.

OT

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i I : ; ; : : : : : : ; : : : : : ; ; ; {

1 2 3 4 5 1 2 3 4 5 2 3 4 5 1 2 3 4 5

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Fig. 7. Radiographic pattern profile of the hands (age 121, according to the method of Poznanski [19741. Circles indicate the left hand, and squares indicate the right hand. Absence of the 5th distal phalanges is reflected by a sharp dip in the profile (dotted lines). The measurements were derived from the original photographs taken for Figure 6A and B.

+METACARPAL+ +PROXIMAL + +MIDDLE+ t DISTAL-

The basis of the neurological variability of the syn- drome is not known. Multiple alleles are likely to exist, each with a potentially different effect on the gene prod- uct. The relationship between the recessive form of the DOOR syndrome and the dominant form, a milder disor- der, also remains to be defined [Goodman et al., 1969; Moghadam et al., 19721. Genotype-phenotype correla- tions will be possible when the DOOR syndrome genes have been cloned and the alleles identified. Clinical classification, until then, may be helpful for informing families of the prognosis for young affected children.

ACKNOWLEDGMENTS H.J.L. gratefully acknowledges support from a March

of Dimes I3asil O’Connor Starter Scholar Award (5-

REFERENCES

FY91-0567, 5-FY92-1216).

Cantwell RJ (1975): Congenital sensori-neural deafness associated with onycho-osteo dystrophy and mental retardation (D.O.O.R. syndrome). Humangenetik 26:261-265.

Feinmesser M , Zelig 13 (1961): Congenital deafness associated with onychodys1;rophy. Arch Otolaryngol 74507-508.

Goodman RM, Lockareff S, Gwinup G (1969): Hereditary congenital deafness with onychodystrophy. Arch Otolaryngol90474-477.

Hess RO, Pecotte J K (1984): Additional case report of the DOOR syn- drome. Am J Med Genet 19:401-405.

DOOR Syndrome 539

Moghadam H, Statten P (1972): Hereditary sensorineural hearing loss associated with onychodystrophy and digital malformations. Can Med Assoc J 107:310-312.

Nevin NC, Thomas PS, Calvert J , Reid MMcC (1982): Deafness, on- ycho-osteodystrophy, mental retardation (DOOR) syndrome. Am J Med Genet 13:325-332.

Patton MA, Krywawych S, Winter RM, Brenton DP, Baraitser M (1987): DOOR syndrome (deafness, onycho-osteodystrophy, and mental retardation): Elevated plasma and urinary 2-oxoglutarate in three unrelated patients. Am J Med Genet 26:207-215.

Poznanski AK (1974): “The Hand in Radiologic Diagnosis.” Phila- delphia: W. B. Saunders, pp 41-45.

Qazi QH, Nangia BS (1984): Abnormal distal phalanges and nails, deafness, mental retardation, and seizure disorder: A new familial syndrome. J Pediatr 104:391-394.

Qazi QH, Smithwick EM (1970): Triphalangy ofthumbs and great toes. Am J Dis Child 120:255-257.

Sanchez 0, Mazas JJM, Ortiz de DeMatos I (1981): The deafness, onycho-osteodystrophy, mental retardation syndrome. Two new cases. Hum Genet 58:228-230.

Thomas PS, Nevin NC (1982): Radiological findings in the DOOR syndrome. Ann Radio1 25:54-58

Walbaum R, Fontaine G, Lienhardt J, Piquet JJ (1970): Surdite famil- iale avec osteeonycho-dysplasie. J Genet Hum 18:lOl-108.