Sudha Rao, M.P. Colaco, M.P. Desai

From Bai Jerbai Wadia Hospital for Children & Institute of Child Health and Research. Acharya Dhonde Marg, Parel, Mumbai, India.

Correspondence to: Dr. Sudha Rao, Lecturer, Division of Pediatric Endocrinology, Department of Pediatrics, Bai Jerbai Wadia Hospital for Children, Acharya Dhonde Marg, Parel, Mumbai 400 012. E-mail: [email protected]

Manuscript received: June 26, 2001; Initial review completed: August 7, 2001;

Revision accepted: August 7, 2002.

 

McCune Albright Syndrome (MCAS) is an association of, Café-au-lait macules, polyostotic fibrous dysplasia and autonomous hyperfunctioning endocrinopathy. This is a rare disorder seen more commonly in females. We evaluated 7 (6F & 1M) cases under six years of age (4 months to 5.5 yrs) presenting with Café-au-lait spots, polyostotic fibrous dysplasia and/or sexual precocity. All the 7 cases had large Café-au-lait spots, radiologic features of polyostotic fibrous dysplasia were seen in 5 cases. Six girls had precocious puberty with large ovarian follicles and elevated S. Estradiol levels (14-65 pg/dl) with prepubertal gonadotropin levels in 5 of them. Medroxy-progrestrone acetate was used to treat the sexual precocity. Five girls on follow up for 6 months (6mo-16mo) showed cessation of menstrual episodes and regression of ovarian follicles in three, regression in breast size in one, and three girls continued to grow at a height velocity >95th centile for age. Skeletal lesions and skin features did not show any change. No other endocrinopathy was noted. Gonadotropin independent precocious puberty was the only endocrine affection seen in this series.

Key words: McCune-Albright syndrome, Café-au-lait spots, Polyostotic fibrous dysplasia.

McCune Albright Syndrome (MCAS) is a heterogeneous clinical condition(1) which is caused by a sporadic, somatic, post zygotic missens mutation in the gene codifying the alpha subunit of Gs protein of the receptor system of most proteic hormones(2). This is a rare syndrome, seen more commonly in females. The classic form is defined by a triad of physical signs: melanotic cutaneous macules called café-au-lait spots, multi-centered but localized osseous lesions termed polyostotic fibrous dysplasia and autonomous hyperfunctioning endocrinopathies(1). The non-classical form consists of only two of these conditions(3,4). Gonadotropin indepen-dent precocious puberty is the commonest endocrine affection described(1,6). Until now, there are no reports of a series of cases of MCAS in Indian literature. We describe here 7 cases of McCune Albright Syndrome (MCAS) referred to the Endocrinology Division of this institution along with a review of litetrature.

Seven children (6F, 1M) under the age of six years (4mo - 5.5yrs) diagnosed to have MCAS on the basis of the presence of café-au-lait spots, radiological evidence of polyostotic fibrous dysplasia, and/or sexual precocity were studied. The presence of typical, irregularly shaped hyperpigmented café-au-lait spots; their number, size, shapes and localization were recorded. The presentation with the development of secondary sexual characteristics prior to the age of 8 years in girls and 9 years in boys was suggestive of sexual precocity. The pubertal signs were assessed based on Tanner’s staging. Skeletal dysplasia recognised at clinical level (pain, gait disturbance, fractures, and deformities) was graded using the Feullian’s score(5). Other associated endocrine and non-endocrine findings were also noted. All the cases were subjected to laboratory investigations. Serum calcium, phosphorous and alkaline phosphatase levels were done in all the cases. Serum FSH, LH and Estradiol / Testosterone levels were done in the cases with clinical evidence of precocious puberty. Specific endocrine investigations viz. T3, T4, TSH, Prolactin levels were done as indicated. Pelvic sonography was done in all girls to assess the uterine size, check for ovarian cysts. Radiography of the limb bones, pelvis and skull was done in all the cases to detect monostotic or polyostotic fibrous dysplasia. Bone scintigraphy could not be done in the children who did not show any radiological changes. Special investigations in the form of echocardiography were done in cases presenting cardiac affection.

Medroxy-progesterone acetate (MPA) was given, in a dose of 150mg, intramuscularly once every 4 weeks in all the girls presenting with sexual precocity and episodes of vaginal bleeding. Periodic follow up at 3 months interval included a detailed clinical evaluation of the progress of puberty, menstrual episodes and growth velocity. Repeat pelvic ultrasound and estimation of estradiol levels was advised in the females.

The age of onset of symptoms ranged between 3mo to 4yr 6mo. Sexual precocity was the commonest endocrine affection seen. Five patients had the characteristic triad of café-au-lait spots, polyostotic fibrous dysplasia and precocious puberty; two cases (case 1 & 4) presented in the non-classical form (Table I). Out of all the six girls who presented with sexual precocity, five had episodes of bleeding per vaginum (Table I). The vaginal mucosa appeared pale with presence of white discharge in all these 6 cases. The café-au-lait spots, seen in all the 7 cases, were restricted to one half of the body (Fig 1). Skeletal involvement was moderate to severe in four cases (Table I). Goiter in two cases (case 1&4) and soft systolic murmur in two cases (case 2 & 5) were the other associated findings. Laboratory investigations (Table I) showed elevated S. Estradiol levels (14-65 pg/dL) in all the 6 girls. Pubertal gonadotropin levels (FSH: 5.2mIU/ml, LH: 7.6IU/ml) was seen in one child (case-4), possibly due to the onset of secondary true precocious puberty. Thyroid profile done in 4 cases was normal. Alkaline phosphatase was uniformly raised, markedly so in the cases with severe skeletal dysplasia.

Fig. 1 Showing the Cafe-au-lait spotts on right side of the face, neck and trunk. Also note the thelarche (Tanner's stage III of breast development).

Table I__Case Description

1

3 yrs 10 mo

3 yrs 3 mo

M

–

G1P1A1

multiple largest

+ genu valgum,

–   

–

generalised

(I)

5cm × 20 cm

# Rt femur,

osteopenia, cortical

left leg, buttock,

# Left tibia

thinning, extensive 

flank, upper

(Severe)

base of skull sclerosis

back

B/L healed # neck Femur

2

2yrs 10 mo

2yrs-T

F

Regular

B3P2A0

several all over

+genu valgum, hip

14.0

Uterus=4.3×

#Rt femur Sclerosis

2yr6mo-B

(III)

the body

dislocation,

2.3×1.5

base skull fibrous

2yr 6mo-H

beading

N endo.echo

dysplasia long bone leg

(Moderate)

Multiple cysts

in ovaries RtOv=

large cyst 4.3×3.5

×3cm LtOv=small

cyst 1.7×0.7cm

3

5yr 6mon

1yr-T

F

Irregular

B2P1A1

Large over

+genu valgum,

48.0

Ut=4.4×2.8

Fibrous dysplasia rt

1yr6mo-B

(II)

spine and

#Rt femur

×1.8 Endo

femur

buttocks

(Severe)

thick=0.6 Lt.Ov

large cyst 3.6×

3.6×2.1 Rt.Ov=

1.2×1.4×0.6

two follicls Rt Ov

4.

4yrs 11mo

4y7mo-B

F

Once

B3P1A1

Irregular 5×4 cm

-beading+

65.2

Ut=4.2×3×1.2 Rt

Rachitic changes+

4yr6mo-T

(III)

over

Ov=2×1.5×2

sacrum.Also

(NIL)

LtOv=not visualised

over inguinal

i.e. small follicles

region

both sides

5.

2Yr 8mo

3mo-T

F

–

B4P1A1

+over face Rt

+ pain

32.0

Ut=4×1 bulky

fibrous dysplasia over

(IV)

trunk

(MILD)

LtOv=1.7×1, Rt OV

rt fibula-lower end

not visualised

6.

4 Mo

3mo-B

F

Once

B2P1A1

large over

(NIL)

22.0

i.e. follicles bulky ut.

–

(II)

buttocks rt back

RtOv-2.2×1.5×1.7

and arm

single large follicle 1cm

dia LtOv-1.2×1.1

7.

2yr8mo

1yr6mo-B

F

Irregular

B2-3P1A1

large on rt face

hemiatrophy waddling

52.0

Ut=4.9×1.6×2.0

fibrous

1yr6mo-T

(II)

8×4cm

 gait genu valgum

Rt Ov-not seen

dysplasia hip

bone pain+ (Moderate)

Lt Ov-2.5×1.6 with

bones and

single follicle=2.4×1.4

neck Rt femur

*B-Bleeding per vaginum, T-Thelarche, H-public hair, $ SMR-Sexual maturity rating, Ov= Ovary							

Pelvic ultrasound in all the girls showed bulky uterus and asymmetric ovarian enlargement with large follicular cysts on presentation (Table I). On radiography polyostotic fibrous dysplasia was seen in 5 cases (Table I) (Fig 2). Bone scintigraphy could not be done in the two cases (Cases 4 & 6) that did not show the radiological evidence.

Fig. 2 Radiological evidence of fibrous dysplasia seen in the neck of left femur.

Five girls received monthly injections of Medroxy-progestrone acetate (MPA) 150 mg. Other drugs like testolactone were not available and/or affordable. All the five girls could be followed up for a period of at least 6 months. A height velocity >95th centile was seen in three cases, (Case-3,4,7), Menstrual episodes did seem to respond in three cases (Case-4,6,7). The breast size remained the same in three (Case-2,3,7), regressed in one (Case-6) and advanced further in one case (Case-4). Appearance of pubic hair was seen in one case. Follow up investigations revealed a fall in repeat S. Estradiol level in three cases (Case-2,6,7), it could not be done in the other two. On the pelvic ultrasound, the uterine dimensions had regressed in 3 cases (Cases 4,6,7). The period of follow up was too short to judge any deterioration in the skeletal affection or to observe any further skin changes. No other endocrine or non-endocrine conditions were seen on follow up.

McCune and Albright (1936) first described the association of café-au-lait pigmented skin lesions and polyostotic fibrous dysplasia with gonadotropin independent precocious puberty. This is a rare disorder seen commonly in females (1,5,6). Out of the 196 cases of precocious puberty seen at our clinic in the last two decades, there were 7 cases that presented as MCAS. MCAS is a sporadic condition caused by a somatic, constitutively activating mutation in the exon 8 of Gs alpha gene codifying the alpha subunit of Gs protein(2,3). This abnormal Gs protein activates the adenylate cyclase system leading to autonomous function of cell proliferation and/or hormonal hypersecretion(6). The clinical expression depends on the number of mutated cells and the affected organs; thus the presentation can be heterogeneous. It can be of early or late onset with slow or quick evolution(2).

Precocious puberty, which is gonadotropin independent (prepubertal gonadotropin levels), is the commonest endocrine affection and occurs due to the autonomous functioning of ovarian cysts causing cyclic estrogen secretion which affects a rapid progression of pubertal characteristics along with accelerated growth and skeletal maturation(7). Breast enlargement and pigmentation occurs with the development of follicular cyst and uterine bleeding occurs with their involution(2,4,7). High circulating estrogen levels increase the sensitivity of androgen responsive organs and can cause growth of genital hair and apocrine sweat gland development despite prepubertal androgen levels(7).

Autonomous hyperfunctioning of other endocrine organs causing hyperthyrodism, occult thyrotoxicosis, hypercortisolism, GH excess, hyperprolactinemia, are described. Thyroid disorder is the second commonest affection seen(3,9). Bone dysplasia, thymic hyperplasia, hepatobiliay disorders, intestinal adenomatous polyp, cardiovascular disorders are some of the non-endocrine manifestations(6,7). Bone dysplasia, can be mono-ostotic or polyostotic. They mostly involve the limb bones. Clinically they present with chronic pain, deformity, limb asymmetry and spontaneous fractures. Distortion of facial features, auditory and visual impairment; due to compression of acoustic and optic nerves respectively can result from fibrous dysplasia of facial bones(8). Plain radiographs may be normal early in life and a technetium bone scan may be required(7).

Café-au-lait macules are large pigmented spots with irregular borders (coast of Maine). They are of different size, number, morphology, age of appearance, usually affecting one half of the body and may indicate active melanocyte proliferation(2). These skin changes may evolve over a period of time.

As the precocious puberty is gonadotropin independent, GnRH analogues have not been found to be useful in the treatment(1). Medroxy-progesterone acetate (MPA) can be used for its local anti-estrogen property. There are not many reports on treatment with MPA in the literature(11). In our series, out of the 5 cases that received MPA, three did not show any progression of pubertal changes. Testolactone, an aromatase inhibitor, in a dose of 40mg/kg/D in divided doses, has recently been shown to be effective in causing a fall in estradiol levels, reduction in menstrual episodes and growth velocity. Adverse effects in the form of abdominal pain, headache, and abnormal liver enzymes are reported(6). Tamoxifene, a nonsteroidal estrogen-antiestrogen, which acts by competitive inhibition at the estrogen receptor level, is used in a dose of 20-40mg/day. Experience of its use is limited(12). Oophorectomy or cyst removal has sometimes been helpful in a rapidly progressing pubertal development(8). Bisphosphonates have been used in the treatment of moderate to severe polyostotic fibrous dysplasia with variable response(13). Other endocrine manifestations need specific treatment.

The authors wish to thank the patients and The Management, Wadia Group of Hospitals for all the help rendered in publishing this work.

Contributors: SR collected, analyzed, drafted the manuscript and will act as the guarantor. MPC and MPD reviewed the subject and helped in analysis and drafting the paper.

Funding: None.

Competing interests: None stated.

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