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Pseudohypoparathyroidism (PHP), Pseudo-pseudohypoparathyroidism (PPHP) or Albright's Hereditary Osteodystrophy (AHO)

by Dr Swift & Dr Shenoy of Leicester Royal Infirmary Childrens Hospital

An Information Leaflet for Parents/Carers

Leicester Royal Infirmary Children's Hospital
University Hospitals of Leicester NHS Trust



All parents hope that their children will be healthy and normal. They are naturally concerned and upset when they find out that their child has a medical condition but anxious to learn more about the condition. You may have been told recently that your child has Pseudohypoparathyroidism or Pseudo-pseudohypoparathyroidism (both also known as Albright's Hereditary Osteodystrophy ) or you may have known this for sometime. In either case, you may still have unanswered questions about this condition. We have prepared this booklet to provide additional help and information. The purpose is to answer a number of the frequently asked questions and to act as a pointer to other sources of information.

We hope this information will give you a better understanding of your child's condition and so help you in looking after your child.



1. What is Pseudohypoparathyroidism (PHP)?

2. What is Pseudo-pseudohypoparathyroidism (PHPP)?

3. What is Albright's Hereditary Osteodystrophy (AHO)?

4. What are the physical and other features of PHP/PHPP?

5. What are the parathyroid glands and parathyroid hormone?

6. What does parathyroid hormone do?

7. How does parathyroid hormone act?

8. What happens when Gsa?L is not working in PHP/PHPP?

9. Why does your child have PHP/PHPP?

10. What is the risk of your next child having PHP/PHPP?

11. Is your grandchild at risk for PHP/PHPP?

12. What tests are available to diagnose PHP/PHPP?

13. Can the doctors be sure that your child has PHP/PHPP?

14. What are the treatment options available?

15. Does the treatment need to be lifelong?

16. Are there family support groups?


1) What is Pseudohypoparathyroidism (PHP)?

The term 'Pseudo' in Greek implies similar to but?enot the same as'.?eHypo' means too little.?eParathyroidism' means related to parathyroid hormone (which controls calcium levels). So, Pseudohypoparathyroidism means?gfalse low parathyroid hormone condition?h.

As calcium levels in the blood were sometimes found to be low, PHP was thought to be due to parathyroid hormone deficiency (hypoparathyroidism). Later it was found that the parathyroid hormone levels were normal or even high.

We now know that these unusual findings of PHP are caused by a failure of the parathyroid hormone to work properly ( or more accurately to signal appropriately? | see later) and so is unable to maintain normal calcium levels in the blood.


2) What is Pseudo-pseudohypoparathyrodism (PHPP)?

Some members of affected families may have similar physical features as PHP, but serum levels of calcium and phosphorous are normal. This variant of PHP is called Pseudo-pseudohypoparathyroidism (PPHP). Here, the defect in parathyroid hormone signal differs from that of PHP resulting in normal blood calcium levels.


3) What is Albright's Hereditary Osteodystrophy (AHO)?

Professor Fuller Albright, an American doctor, first described this condition in 1942. Hereditary' implies either being born with a condition or the inheritance of a condition from parent to child through the genes. The word?eosteo' means bone;?edystrophy' means changes or abnormalities.

AHO is the collective term for the physical features that children with PHP and PPHP have and is sometimes used instead of PHP or PHPP.


4) What are the physical and other features of PHP and PPHP?

PHP and PPHP affects people in many different ways. Some children and adults are affected very minimally, some moderately and some more severely. Some of the commonly described physical features are given below. Individuals do not necessarily have all the features for a diagnosis to be made.

Usually heavy, stocky build and most often short. Occasionally normal stature but overweight. Exact cause of overweight and short stature are not known. Advanced bone maturation during childhood is recognised as a contributory factor for short adult stature.

Round face with low flattened nasal bridge

Bony changes in hands and feet involving:

Short bones in fingers and toes giving short stubby hands and feet (Fig 1)

Short bones in palm of hand ( the metacarpals) usually corresponding to 4th and 5th fingers. ( Fig 2)

On making a fist this gives a dimpling instead of a prominence on back of hand at the 4th and 5th knuckles (Fig 3). Index finger is rarely involved making index finger sometimes longer than middle finger.

Short bones in the feet ( the metatarsals ) usually corresponding to 3rd and 4th toes (Fig 4)

Bony swellings, bowing of bones


Figure 1 : Hand of a child with AHO showing short stubby fingers


Figure 2: Hands of a child with AHO showing marked shortening of the fourth metacarpal in the right hand and third metacarpal in the left hand

Figure 3: Hands of an adult with AHO showing knuckle dimples in the clenched fists

Figure 4: Feet of a child with AHO showing extreme shortening of the metatarsals corresponding to the 3rd and 4th toes.

Learning difficulties in varying severity?| difficulties could be specific learning or across the range. Extra help on a one-to-one basis in school may be needed.

Calcification (hard swellings) under the skin.

Cataract formation

Dental- thin enamel, delayed eruption or permanent teeth

In girls- delay in the onset of puberty and periods, menstrual irregularities like absent or scanty periods

In boys- delay in the onset of puberty

Fertility problems in later life? | subnormal fertility can be feature in both boys and girls.


5) What are the parathyroid glands and parathyroid hormone?

The parathyroids are glands in the neck lying close to or within another gland called the thyroid gland. The thyroid gland lies in the front of the neck just below Adam's apple. Parathyroid glands produce the hormone called parathyroid hormone.


6) What does parathyroid hormone do?

Hormones are chemical messengers that carry information to different parts of the body. Parathyroid hormone is responsible for maintaining normal calcium levels in the blood. Calcium is needed to maintain normal structure of bone and teeth and also helps in contraction of muscles. These are just two of the many important functions of calcium in our body.


7) How does parathyroid hormone act?

When blood calcium levels are low, parathyroid hormone is released from the parathyroid glands. Parathyroid hormone (along with Vitamin D) acts on bone and intestine to increase blood calcium levels. Parathyroid hormone needs to convey messages to the inside of cells that the blood calcium levels are low so that cells can release more calcium into the blood. This is achieved through parathyroid hormone attaching to a receptor on the cell wall which then opens the cell wall. This process also requires another component called messenger (G protein). G proteins are family of proteins with three subtypes Gs alpha, Gs beta and Gs gamma - s stands for stimulatory.

In PHP and PHPP, the real defect is an abnormality in the activity of Gs alpha messenger resulting in failure of parathyroid hormone to signal or convey the message to the inside of cells.


8) What happens when Gs alpha is not working in PHP/PPHP?

In PHP, parathyroid hormone is released appropriately in anticipation of elevating low blood calcium levels. However, due to the defect in Gs alpha messenger, the message is not conveyed to the inside of the cell. This results in failure of the cell to release calcium into the blood and correct the low calcium levels. As a result, messages are sent to the parathyroid gland to produce more parathyroid hormone in an attempt to normalise calcium levels. Thus, parathyroid hormone levels are inappropriately high in the presence of low calcium levels.

In PPHP, although the defect in Gs alpha messenger is similar to that in PHP, blood calcium levels are normal and reason for this is unclear.

Gs alpha is also important in controlling the way in which other hormones work, including thyroid stimulating hormone (TSH) and sex stimulating hormones- luteinising hormone (LH) and follicle stimulating hormone (FSH). TSH signalling defect may result in some features of an underactive thyroid hormone. Sex stimulating hormones are necessary for the onset of puberty and maintenance of sexual development in boys and girls resulting in delay in the onset of puberty and fertility problems later in life.


9) Why does your child have PHP/PPHP?

Our blueprint for life, known as inherited material or DNA, is packaged into chromosomes. We have 23 pairs of chromosomes, one set inherited from each parent. Each member of the pair consists of blocks of DNA forming?egenes'. Genes provide instructions to the body with details of how and when activities should take place.

G proteins are each made by a separate gene. Gs alpha is made by the GNAS gene on chromosome 20.

The genetic problem in PHP/PPHP is a copying error (often called mutation) in the GNAS gene. This leads to alterations in the normal activity of the Gs alpha protein and impaired ability of the body to respond to the normal hormone/receptor signals.

A child is born with PHP or PPHP because the gene mutation is either passed on from one of the parents or a new mutation has been formed when the baby was conceived.

There is some evidence to suggest that Gs alpha mutation is paternally transmitted in PPHP and maternally transmitted in PHP.


10) What is the risk of your next child having PHP/PPHP?

This will depend upon a number of factors. The most important being dependant upon whether genetic alterations that cause altered G-protein activity in your child are also present in yourselves and this can be investigated these days with a DNA test.

If you as parents do not have a genetic abnormality, your child must have had a new mutation and your next child will have the same risk as general population and not higher.

If, on the other hand, if either of you have the same genetic abnormalities, there is a 50% chance of passing on the condition to another boy or girl child.


11) Is your grandchild at risk for PHP/PPHP?

In view of the clinical condition, your child may have problems with fertility in the first instance. As your son or daughter has the genetic mutation, your grandchild has a 50% chance of inheriting the condition.


12) What tests are available to diagnose PHP/PHPP?

In addition to the above physical features blood tests, urine tests, X-rays and genetic tests can help in the diagnosis of PHP/PHPP.

Blood tests may reveal low calcium, elevated parathyroid hormone, thyroid stimulating hormone(TSH), follicle stimulating hormone (FSH) and lutinising hormone (LH) levels. Sometimes, low thyroid hormone and sex hormone levels may be identified.

Specialised urine tests occasionally help in showing deficient PTH action on cells.

X-ray of the hand and feet may demonstrate short bones in the palm of the hand (metacarpal) and feet (metatarsal). (Figure 5)

Genetic tests using blood samples to examine DNA demonstrates genetic mutation of the GNAS gene on chromosome 20.

Figure 5: X-ray of the hand in a child with AHO demonstrating extreme shortening of the 4th palm bone (metacarpal).


13) Can the doctors be sure that your child has PHP/PPHP?

Usually a specialist can recognise the physical characteristics. Also, there are genetic tests available, which are only performed in a few specialised laboratories in the UK and other countries and the results may take weeks or months to be available. These DNA tests are of course helpful if positive, but negative results (no mutations found) do not totally exclude the diagnosis.


14) What are the treatment options available?

If calcium levels are low, vitamin D and calcium can be given as tablets to improve this.

If an underactive thyroid gland is diagnosed, thyroxine tablets are needed.

On rare occasions, abnormalities of sex hormones like follicle stimulating hormone (FSH) and luteinising hormone ( LH) require hormone treatment if there is delay in onset of puberty. Puberty can be induced with testosterone for boys and oestrogen for girls. Further changes (testicular growth in boys, menstruation in girls) may happen without the continuation of hormone treatment. In a few children, continued oestrogen (girls) or testosterone (boys) may be necessary to maintain sexual development.

Fertility problems: in adulthood, when an individual has problems with fertility, hormonal injections to induce fertility may be required which requires referral to a doctor(endocrinologist/gynaecologist) who specialises in fertility problems.

Learning difficulties: school development and progress needs monitoring and special educational help is sometimes required.

Cataract: control of low calcium levels might arrest their progression. If any visual difficulties occur, referral to an eye specialist is required.


15) Does the treatment need to be lifelong?

Calcium/vitamin D treatment is lifelong. Other hormonal treatment may be required such as lifelong thyroid treatment or sex hormones to maintain sexual development.


16) Are there family support groups?

Yes. They are:

CGF (The Child Growth Foundation)
Registered Charity No. 274325
2 Mayfield Avenue
London W4 1PW
Tel: +44 (0)20 8995 0257/ 8994 7625
Email: cgflondon@aol.com

CLIMB (Children Living with Inherited MetaBolic Diseases)
176 Nantwich Road
Cheshire CW2 6BG
Tel: 0800 652 3181

2835 Salmon
Idaho Falls
Idaho 83406
Tel: 001 208 524 3857

It may be helpful to speak to or meet another family who has a similar affected child with PHP. The best way to organise this is to speak to your child's Geneticist, Paediatrician, other Specialists or through family support groups.



We hope this booklet has helped you understand your child's condition and answered some of your questions. We have tried to cover most of the important points. If you have any further questions you can always contact your child's Specialist or Consultant for further advice.



We are grateful to Professor Richard C Trembath (Geneticist) and Mrs.Vreli Fry (Child Growth Foundation) for their valuable comments and encouragement in preparation of this booklet.

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