American Journal of Medical Genetics 35:383-387 (1990)

Previously Unrecognized Congenital Progeroid Disorder Elizabeth M. Petty, Renata Laxova, and Hans-Rudolf Wiedemann Departments of Pediatrics and Genetics, University of Wisconsin-Madison Medical School, Madison (E.M.P., R.L.); Department of Pediatrics, University of Kiel, Kiel, Federal Republic of Germany (H.-R. W.)

We report on a 5-year-old girl with a progeroid disorder and compare her to a previously re- ported woman now in her forties, whom she resembles to a striking degree. Common man- ifestations include pre- and post-natal growth retardation, markedly diminished sub- cutaneous fat, wrinkled skin, abnormally scant hair growth, hypoplastic distal pha- langes with hypoplastic nails, umbilical her- nia, large open anterior fontanelle, and nor- mal cognitive and motor development. Both patients have had a prematurely aged ap- pearance since birth. These 2 patients appear so different from previously reported patients with progeroid disorders that they may repre- sent a separate entity.

KEY WORDS: progeroid, wrinkled skin, ab- normal nails, scant hair, growth retardation

INTRODUCTION Progeria, or Hutchinson-Gilford syndrome, is a rare

but characteristic “premature aging” disorder. In addi- tion there is a relatively large group of so-called “pro- geroid” (progeria-like) syndromes or disorders. Some patients with these syndromes have been mistakenly diagnosed as having progeria [Wiedemann, 19871.

Here we report on a girl who had congenital progeroid manifestations and whose clinical picture was not sug- gestive of any previously known disorder. However, she did bear a striking resemblance to a female patient who has been followed by one of us (H.-R.W.) since 1946 and mentioned in several reports ([Wiedemann 1948a,b, 1969, 19791.

Received for publication March 30, 1989; revision received July 26, 1989.

Address reprint requests to Renata Laxova, M.D., Ph.D., Wis- consin Clinical Genetics Center, Waisman Center, Room 337, Uni- versity of Wisconsin, Madison, WI 53705-2280.

CLINICAL REPORTS Patient 1

We first saw patient J .A. a t age 18 months when she was referred because of small stature and an unusual appearance. (Fig. lA,B). She was white with a height, weight, and head circumference of 70 cm (mean for 9 months), 5.9 kg (mean for 4 months), and 42.2 cm (mean for 6.5 months), respectively. Her cephalic index was 1.0, reflecting her unusually round head shape. Physical manifestations included large, wide calvaria, broad forehead, wide metopic suture, and large anterior fon- tanelle (6 x 15 cm). In contrast to her cranial vault her face appeared relatively small with small, posteriorly angulated, apparently low-set ears, gray irides, short palpebral fissures, epicanthal folds, left esotropia, thick, dark eyebrows and eyelashes, a prominent mandible and lower lip, relatively thin upper lip, normal palate, slightly long upper lip, and only 2 abnormally shaped erupted teeth. Dry, brittle, wispy light brown hair cov- ered her scalp in an irregular fashion with bilateral whorls. Mild hirsutism extended down her back. Her smooth skin, without atrophy or abnormal pigmenta- tion, was notably wrinkled and markedly redundant, especially in the neck and truncal regions. Turgor was mildly decreased over the abdomen but otherwise nor- mal. Superficial veins were easily visible, and 2 fading scalp hemangiomas were present. The absence of sub- cutaneous fat was striking, especially in the truncal region, where there were symmetrical dimples in the acromial and suprascapular regions. Cardiopulmonary system was normal. She had a large protruding umbili- cal hernia but no liver or spleen enlargement. Genitalia were normal. A small pilonidal dimple was noted near her slightly anteriorly placed anus. Musculoskeletal ab- normalities include underossified calvaria and short distal phalanges bilaterally with absent distal flexion creases and limited flexion of distal phalanges in some of her fingers. Nails were either hypoplastic or absent (Fig. 2A,B); long bones were grossly normal with a normal range of motion. Apart from left esotropia, her neuro- logical status was normal with good muscle bulk and strength and symmetrically brisk deep tendon reflexes.

J.A. was seen for follow-up at age 5 years (Fig. 3A,B) with a height, weight, and head circumference of 92 cm (mean for 31 months), 10 kg (mean for 14 months), and 45 cm (mean for 10.5 months), respectively. Her head

0 1990 Wiley-Liss, Inc.

384 Petty et al.

Fig. 1. A,B: J.A. at age 18 months.

Fig. 2. A J.A. at age 18 months: hands. B: J.A at age 18 months: feet.

Unrecognized Progeroid Disorder 385

Fig. 3. A,B: J.A. at age 5 years

shape was still round with a cephalic index of .99, and her physical findings generally unchanged. Her hair was now longer, lighter, but still brittle, sparse, and irregularly distributed. Eyebrows remained prominent and she had received glasses for hyperopia. Hirsutism was more pronounced and involved her thighs and back. Her skin, with a light, even summer tan, remained wrinkled and redundant. Cardiopulmonary system, neurological status and abdominal organs were normal. The umbilical hernia had been repaired. Her musculo- skeletal system was unchanged and she had no sub- cutaneous fat.

Past Medical History J.A. was born at term of a 24-year-old gravida 2, para

2 healthy woman and 28-year-old healthy man who de- nied consanguinity. Family history was unremarkable. The pregnancy was uncomplicated but the mother gained only 2.7 kg. She smoked ll!z packs of cigarettes per day. Apgar scores were 6 and 9 at one and 5 minutes, respectively. The infant was small for gestational age, with height, weight, and head circumference of 42 cm, 1,670 g and 29.5 cm, respectively. Due to her size she was transferred to a level I11 nursery, from which she was discharged at age 20 days, weighing 1,860 g. During her hospital course she had mild apneic spells and an Escherichia coli urinary tract infection.

J.A.'s growth was markedly diminished with a grad- ual deceleration of weight and head circumference more than height.

Her development was normal during infancy. Most recently, at age 4Y/i2 years, her preschool developmental profile skills ranged between 4 years and 5.5 years with some difficulty in fine motor skills and visual spatial perception. Socially, she has always been shy but friendly.

J.A. had no major medical problems. Diagnostic studies have included: normal chromosomes (46,XX) (including prometaphase banding); normal quantita- tive serum and urine amino acids; normal biotinidase levels; normal neonatal biochemical screening results and IgM levels; normal immunoglobulins, including IgG subclasses; normal thyroid function tests; normal cop- per, zinc, and iron levels; repeatedly normal complete blood counts; normal chemistry surveys, including cho- lesterol and triglyceride levels; and normal protein elec- trophoresis. Results of EM studies of her skin were nor- mal; EM studies of her hair showed distal destruction of the cuticle, with rare structural abnormalities and green-stick fractures. Cultured fibroblasts showed nor- mal growth and proliferation. Radiographic studies have shown evidence of a peculiar skeletal dysplasia involving the axial skeleton with normal long bones; bone scans were remarkable for a peculiar underossified appearance of her calvaria; convexity of the lumbar spine to the right with partial L5 sacralization on the left; normal chest and abdominal films; normal IVPs; a normal head CT neonatally. Cardiology work-up was normal with normal ECGs and echocardiograms. Oph- thalmological evaluations showed hyperopia, left eso-

386 Petty et al.

tropia, and mild recent corneal scarring following an infection.

Patient 2 U.P., also a female, was first evaluated in 1946 at age

3 years (Fig. 4) and intermittently since that time. Her clinical features, which resembled strikingly those of J.A., are given in Table I. At last follow-up, in 1988, U.P. was 45 years old. She had worked as a secretary and later as a housewife. She had been married for 28 years, had never conceived, and was widowed. She was living independently with no cardiac or joint problems. She wore dentures, glasses, and a wig. Her height was 146 cm, weight 35 and 39 kg (1968 and 1988, respectively) and head circumference 51 cm. She appeared unusual and older than her age, but her appearance had not changed significantly since her previous evaluation at age 18 years (Fig. 5).

DISCUSSION Both J.A. and U.P. had manifestations similar to pa-

tients with the Wiedemann-Rautenstrauch syndrome (WRS) (Table I) [Wiedemann, 19791. Up to now 6 pa- tients with this syndrome have been reported [Rudin et al., 19881. Like J.A. and U.P., patients with WRS are born SGA, with manifestations of a premature aging disorder, including lack of subcutaneous fat; a wide per- sistent anterior fontanelle (AF); grossly underossified calvaria; sparse, thin hair; and delayed, abnormal denti- tion. Unlike J.A. and U.P.? patients with WRS have natal teeth and large hands and feet with long, tapering digits. Most are developmentally delayed or neuro- logically impaired.

The clinical resemblance between J.A. and U.P. was so striking that we suggested that the 2 patients repre- Fig. 4. A,B: U.P. at age 3 years. C: U.P. at age 3 years: hands.

Fig. 5. U.P. at age 18 years (no wig).

Unrecognized Progeroid Disorder 387

TABLE I. Comparison of Characteristics in Patients With Wiedemann-Rautenstrauch Syndrome With Those Present in the Patients Reported Here

Wiedemann-Rautenstrauch syndrome [From Wiedemann, 1979; Rudin et Patient 1 Patient 2

Manifestation al., 19881 (J.A.) (U.P)

Birth at term SGA Birth weight Birth length Birth head circumference Round head shape Widely open sutures Persistent fontanelle Prominent scalp veins Sparse scalp hair Small, apparently low-set ears Relative hypoplasia of the facial bones “Progeroid’ face No cataracts Natal incisors Large hands and feet

Short distal phalanges

Decreased subcutaneous fat Wrinkled redundant skin Mild hirsutism Umbilical hernia at birth Growth severely retarded Development

Delayed with mental retardation Average or above

Normal cardiopulmonary examination Neurological examination

with long fingers and toes

with aplastic or hypoplastic nails

Normal Abnormal

+ 616 + 616

2,100-2,550 g 45-49 cm

+ 616 + 616

+ 616 + 616 + 616 + 616 + 616 + 616

+ 4-616

+ 616 + 5-616 + 5-616

-

+ 616 + ?

+ 616

416

?

-

516

+ +

1,670 g 42 cm

29.5 cm + + + + + + ? + + -

~

-

+ + + + + + +

+ + +

+ +

1,850 45 cm 31 cm +

+ + + + + ? + + -

-

-

+ + + + + + + -

+ + +

sented a separate entity, namely, a previously unrecog- nized congenital progeroid syndrome. This syndrome must be of genetic origin, although its pathophysiology and mode of inheritance are unknown. Continued obser- vation and evaluation of these 2 patients, as well as of additional patients with the same characteristics, will provide more information about the natural history of the disorder. If the clinical course observed in U.P. is characteristic, i t seems that, in contrast to most other premature aging disorders, some degree of improve- ment can be expected in patients who have the entity described here.

ACKNOWLEDGMENTS The authors are indebted t o Dr. John Hoggatt of

Neenah, Wisconsin, for referring patient J.A. and for participating in her evaluations. We are also grateful to the patient’s mother for permitting us to write a report

about her daughter and to Dr. John Opitz for recognizing the similarities between J.A. and U.P.

As always, we wish to thank Susan Johnson for typing the manuscript so willingly and perfectly.

REFERENCES Rudin C, Thonimen L, Fliegel C, Steinmann B, Buhler V (1988): The

neonatal pseudo-hydrocephalic progeroid syndrome. (Wiedernann- Rautenstrauch). Eur J Pediatr 147:433-438.

Wiedemann H-R (1948a): Uber Greisenhaftigkeit im Kindesalter, insbesondere die Gilfordsche Progerie. Z Kinderheilkd 65670- 697.

Wiedemann H-R (1948h3: Progerie. Arch Kinderheilkd 135:169-178. Wiedemann H-R (1969): h e r einige progeroide Krankheitsbilder und

deren diagnostische Einordnung. 2 Kinderkeilkd lO’i:91-106. Wiedemann H-R (1979): An unidentified neonatal progeroid syndrome:

Follow-up report. Eur J Pediatr 130:65-70. Wiedemann H-R (1987): Progeria. In Gornez MR, Adams RD (eds):

“Neurocutaneous Diseases. A Practical Approach.” London: Butter- worths, pp 247-253.